Neuroinflammatory Mechanisms and Vocalization Biomarkers in the Pink1-/- Preclinical Model of Parkinson's Disease

Main Article Content

Sarah A. Lechner Cynthia A. Kelm-Nelson

Abstract

Parkinson's disease is a progressive neurodegenerative disorder with an unclear etiology and a long preclinical phase. The multitude of challenges of studying this in humans highlight the need for robust preclinical animal models that accurately reflect the disease's preclinical progression. While traditional neurotoxin models fail to capture the slow, genetic nature of PD, genetic models, such as the phosphatase and tensin homolog-induced putative kinase 1 (Pink1-/-) knockout rat, offer a preclinical, translational approach. This review synthesizes the current understanding of the Pink1-/- rat model, focusing on two key aspects: neuroinflammation and vocalization deficits. The Pink1-/- rat presents early non-motor symptoms, including vocalization deficits, which can serve as a non-invasive, objective, and longitudinal biomarker of disease progression. This review further proposes a direct link between the model's neuroinflammatory profile, characterized by chronic glial activation and the upregulation of inflammatory pathways, and the observed vocal dysfunctions. By bridging these two critical areas, neuroinflammation as a pathological mechanism and vocalizations as a functional readout, this review provides a framework for future investigations into the diagnosis and treatment of Parkinson’s disease and suggests that targeting specific inflammatory pathways could be a viable therapeutic strategy.

Keywords: Parkinson disease, rat, biomarker, neuroinflammation, ultrasonic vocalization

Article Details

How to Cite
LECHNER, Sarah A.; KELM-NELSON, Cynthia A.. Neuroinflammatory Mechanisms and Vocalization Biomarkers in the Pink1-/- Preclinical Model of Parkinson's Disease. Medical Research Archives, [S.l.], v. 13, n. 10, oct. 2025. ISSN 2375-1924. Available at: <https://esmed.org/MRA/mra/article/view/6972>. Date accessed: 05 dec. 2025. doi: https://doi.org/10.18103/mra.v13i10.6972.
Section
Review Articles

References

1. Feigin VL, Abajobir AA, Abate KH, et al. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet Neurology. 2017;16(11):877-897.

2. Willis AW, Roberts E, Beck JC, et al. Incidence of Parkinson disease in North America. npj Parkinson's Disease. 2022/12/15 2022;8(1):170. doi:10.1038/s 41531-022-00410-y

3. Dorsey ER, Bloem BR. The Parkinson Pandemic —A Call to Action. JAMA Neurology. 2018;75(1):9-10. doi:10.1001/jamaneurol.2017.3299

4. Dorsey E, Sherer T, Okun MS, Bloem BR. The emerging evidence of the Parkinson pandemic. Journal of Parkinson's disease. 2018;8(s1):S3-S8.

5. Yang W, Hamilton JL, Kopil C, et al. Current and projected future economic burden of Parkinson’s disease in the U.S. npj Parkinson's Disease. 2020/ 07/09 2020;6(1):15. doi:10.1038/s41531-020-0117-1

6. Braak H, Tredici KD, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging. 3// 2003;24(2):197-211. doi:10.1007/s00 441-004-0956-9

7. Braak RH, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell and Tissue Research. 2004;318:121-134. doi:10.1007/ s00441-004-0956-9

8. Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism & Related Disorders. 2010;16(2):79-84. doi:10.1016/j.parkrel dis.2009.08.007

9. Schapira AHV, Chaudhuri KR, Jenner P. Non-motor features of Parkinson disease. Nature Review Neuroscience. 2017;18(7):435-450. doi:10. 1038/nrn.2017.62

10. Ciucci MR, Grant LM, Rajamanickam ES, et al. Early identification and treatment of communication and swallowing deficits in Parkinson disease. Semin Speech Lang. Aug 2013;34(3):185-202. doi:10.105 5/s-0033-1358367

11. Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nature Review Neuroscience. 2002;3(7):574-579. doi:10.1038/nrn877

12. Kelm-Nelson CA, Lechner SA, Lettenberger SE, et al. Pink1(-/-) rats are a useful tool to study early Parkinson disease. Brain Commun. 2021;3(2) :fcab077. doi:10.1093/braincomms/fcab077

13. Jia F, Fellner A, Kumar KR. Monogenic Parkinson's Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing. Genes (Basel). Mar 7 2022;13(3)doi:10.3390/genes13030471

14. Yamakado H, Takahashi R. Experimental Animal Models of Prodromal Parkinson’s Disease. Journal of Parkinson’s Disease. 2024;14(s2):S369-S379. doi:10.3233/jpd-230393

15. Bezard E, Przedborski S. A tale on animal models of Parkinson's disease. Movement Disorders. 2011;26(6):993-1002. doi:10.1002/mds.23696

16. Campos FL, Carvalho MM, Cristovao AC, et al. Rodent models of Parkinson's disease: beyond the motor symptomatology. Frontiers in behavioral neuroscience. 2013;7:175. doi:10.3389/fnbeh.2013.00175

17. Helley MP, Pinnell J, Sportelli C, Tieu K. Mitochondria: a common target for genetic mutations and environmental toxicants in Parkinson’s disease. Frontiers in genetics. 2017;8:301198.

18. Yu L, Hoffer A, Hoffer B, Qi X. Mitochondria: A Therapeutic Target for Parkinson’s Disease?[J]. Int J Mol Sci. 2015;16:20704-20730.

19. Chai C, Lim K-L. Genetic insights into sporadic Parkinson's disease pathogenesis. Curr Genomics. 2013;14(8):486-501. doi:10.2174/1389202914666 131210195808

20. Bonifati V, Rohé CF, Breedveld GJ, et al. Early-onset parkinsonism associated with PINK1 mutations: Frequency, genotypes, and phenotypes. Neurology. 2005;65(1):87-95. doi:10.1212/01.wnl.0000167546 .39375.82

21. Kawajiri S, Saiki S, Sato S, Hattori N. Genetic mutations and functions of PINK1. Trends in pharmacological sciences. 2011;32(10):573-80. doi:10.1016/j.tips.2011.06.001

22. Ibáñez P, Lesage S, Lohmann E, et al. Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa. Brain. Mar 2006;129(Pt 3):686-94. doi:10.1093/ brain/awl005

23. Valente EM, Abou-Sleiman PM, Caputo V, et al. Hereditary early-onset Parkinson's disease caused by mutations in PINK1. Science. May 21 2004;304 (5674):1158-60. doi:10.1126/science.1096284

24. Broadfoot CK, Hoffmeister JD, Lechner SA, et al. Tongue and laryngeal exercises improve tongue strength and vocal function outcomes in a Pink1-/- rat model of early Parkinson disease. Behav Brain Res. Mar 5 2024;460:114754. doi:10.1016/j.bbr. 2023.114754

25. Glass TJ, Kelm-Nelson CA, Russell JA, et al. Laryngeal muscle biology in the Pink1-/- rat model of Parkinson disease. Journal of Applied Physiology. May 2019;126(5):1326-1334. doi:10.11 52/japplphysiol.00557.2018

26. Glass TJ, Kelm-Nelson CA, Szot JC, Lake JM, Connor NP, Ciucci MR. Functional characterization of extrinsic tongue muscles in the Pink1-/- rat model of Parkinson disease. PLoS One. 2020;15 (10):e0240366. doi:10.1371/journal.pone.0240366

27. Krasko MN, Szot J, Lungova K, et al. Pink1-/- Rats Demonstrate Swallowing and Gastrointestinal Dysfunction in a Model of Prodromal Parkinson Disease. Dysphagia. Oct 2023;38(5):1382-1397. doi:10.1007/s00455-023-10567-0

28. Grant LM, Kelm-Nelson CK, Hilby BL, et al. Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 knockout rat model of Parkinson disease. J Neurosci Res. 2015;93(11):1713-27. doi:10.1002/ jnr.23625

29. Cullen KP, Grant LM, Kelm-Nelson CA, et al. Pink1−/− rats show early-onset swallowing deficits and correlative brainstem pathology. Dysphagia. 2018;doi:10.1007/s00455-018-9896-5

30. Zhi L, Qin Q, Muqeem T, et al. Loss of PINK1 causes age-dependent decrease of dopamine release and mitochondrial dysfunction. Neurobiol Aging. Mar 2019;75:1-10. doi:10.1016/j.neurobiol aging.2018.10.025

31. Zhao J, Chen Y, Zhi L, Xu Q, Zhang H, Li C. Loss of PINK1 Causes Age-dependent Mitochondrial Trafficking Deficits in Nigrostriatal Dopaminergic Neurons Through Aberrant Activation of p38 MAPK. bioRxiv. 2025:2024.07.17.602426. doi:10.1 101/2024.07.17.602426

32. Wood-Kaczmar A, Gandhi S, Yao Z, et al. PINK1 Is Necessary for Long Term Survival and Mitochondrial Function in Human Dopaminergic Neurons. PLoS One. 2008;3(6):e2455. doi:10.1371 /journal.pone.0002455

33. Kannarkat GT, Boss JM, Tansey MG. The role of innate and adaptive immunity in Parkinson's disease. J Parkinsons Dis. 2013;3(4):493-514. doi: 10.3233/jpd-130250

34. Esposito E, Di Matteo V, Benigno A, Pierucci M, Crescimanno G, Di Giovanni G. Non-steroidal anti-inflammatory drugs in Parkinson's disease. Exp Neurol. Jun 2007;205(2):295-312. doi:10.1016/j. expneurol.2007.02.008

35. Tiwari PC, Pal R. The potential role of neuroinflammation and transcription factors in Parkinson disease. Dialogues in clinical neuroscience. 2017;19(1):71-80.

36. McGeer PL, Itagaki S, Boyes BE, McGeer E. Reactive microglia are positive for HLA‐DR in the substantia nigra of Parkinson's and Alzheimer's disease brains. Neurology. 1988;38(8):1285-1285.

37. MacPherson MK, Huber JE, Snow DP. The intonation-syntax interface in the speech of individuals with Parkinson's disease. Journal of speech, language, and hearing research : JSLHR. 2011;54(1):19-32. doi:10.1044/1092-4388(2010/09-0079)

38. Lyons KE, Hubble JP, Troster AI, Pahwa R, Koller WC. Gender differences in Parkinson's disease. Clin Neuropharmacol. 1998;21(2):118-21.

39. Hertrich I, Ackermann H. Gender-specific vocal dysfunctions in Parkinson's disease: electroglottographic and acoustic analyses. The Annals of otology, rhinology, and laryngology. 1995;104(3):197-202.

40. Rahn DA, Chou M, Jiang JJ, Zhang Y. Phonatory impairment in Parkinson's disease: evidence from nonlinear dynamic analysis and perturbation analysis. J Voice. 2007;21(1):64-71. doi:10.1016/j.jvoice.2005.08.011

41. Skodda S, Rinsche H, Schlegel U. Progression of dysprosody in Parkinson's disease over time--a longitudinal study. Mov Disord. 2009;24(5):716-22. doi:10.1002/mds.22430

42. Holmes RJ, Oates JM, Phyland DJ, Hughes AJ. Voice characteristics in the progression of Parkinson's disease. International journal of language & communication disorders / Royal College of Speech & Language Therapists. 2000;35(3):407-18.

43. Scott B, Borgman A, Engler H, Johnels B, Aquilonius SM. Gender differences in Parkinson's disease symptom profile. Acta Neurol Scand. 2000; 102(1):37-43. doi:10.1034/j.1600-0404.2000.102001037.x

44. Gillies GE, Pienaar IS, Vohra S, Qamhawi Z. Sex differences in Parkinson’s disease. Front Neuroendocrinol. 2014;35(3):370-384. doi:10.101 6/j.yfrne.2014.02.002

45. Elbaz A, Bower JH, Maraganore DM, et al. Risk tables for parkinsonism and Parkinson's disease. J Clin Epidemiol. Jan 2002;55(1):25-31.

46. Shulman LM, Bhat V. Gender disparities in Parkinson's disease. Expert Rev Neurother. 2006;6(3):407-16. doi:10.1586/14737175.6.3.407

47. Wooten GF, Currie LJ, Bovbjerg VE, Lee JK, Patrie J. Are men at greater risk for Parkinson’s disease than women? J Neurol Neurosurg Psychiatry. 2004;75(4):637-639. doi:10.1136/jnnp.2003.020982

48. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity. American Journal of Epidemiology. 2003;157(11):1015-22. doi:10. 1093/aje/kwg068

49. Dave KD, De Silva S, Sheth NP, et al. Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease. Neurobiology of Disease. 2014;70(0):190-203. doi: 10.1016/j.nbd.2014.06.009

50. Kelm-Nelson CA, Brauer AFL, Barth KJ, et al. Characterization of early-onset motor deficits in the Pink1 -/- mouse model of Parkinson disease. Brain research. 2017;1(1680):1-12. doi:10.1016/j.brainre s.2017.12.002

51. Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci. 2002;3(7):574-579. doi:10. 1038/nrn877

52. Knutson B, Burgdorf J, Panksepp J. Ultrasonic vocalizations as indices of affective states in rats. Psychological Bulletin. 2002;128(6):961-977. doi:1 0.1037/0033-2909.128.6.961

53. Brudzynski SM. Communication of adult rats by ultrasonic vocalization: Biological, sociobiological, and neuroscience approaches. ILAR Journal. 2009; 50(1):43-50. doi:10.1093/ilar.50.1.43

54. Brudzynski SM. Ethotransmission: communication of emotional states through ultrasonic vocalization in rats. Curr Opin Neurobiol. 2013;23(3):310-7. doi:10.1016/j.conb.2013.01.014

55. Brudzynski SM, Pniak A. Social contacts and production of 50-kHz short ultrasonic calls in adult rats. J Comp Psychol. 2002;116(1):73-82. doi:10.10 37/0735-7036.116.1.73

56. Brudzynski SM. Principles of rat communication: Quantitative parameters of ultrasonic calls in rats. Behav Genet. 2005/01/01 2005;35(1):85-92. doi:10 .1007/s10519-004-0858-3

57. Wöhr M, Houx B, Schwarting RKW, Spruijt B. Effects of experience and context on 50-kHz vocalizations in rats. Physiol Behav. 2008;93(4–5):766-776. doi:10.1016/j.physbeh.2007.11.031

58. Wöhr M, Schwarting RW. Affective communication in rodents: ultrasonic vocalizations as a tool for research on emotion and motivation. Cell Tissue Res. 2013;354(1):81-97. doi:10.1007/s00441-013-1607-9

59. Kelm-Nelson CA, Lenell C, Johnson AM, Ciucci MR. Chapter 4 - Laryngeal Activity for Production of Ultrasonic Vocalizations in Rats. In: Brudzynski SM, ed. Handbook of Behavioral Neuroscience. Elsevier; 2018:37-43.

60. Riede T. Subglottal pressure, tracheal airflow, and intrinsic laryngeal muscle activity during rat ultrasound vocalization. Journal Article. J Neurophysiol. 2011;106(5):2580-2592. doi:10.115 2/jn.00478.2011

61. Riede T. Stereotypic laryngeal and respiratory motor patterns generate different call types in rat ultrasound vocalization. J Exp Zool A Ecol Genet Physiol. Apr 2013;319(4):213-24. doi:10.1002/jez.1785

62. Riede T, Borgard HL, Pasch B. Laryngeal airway reconstruction indicates that rodent ultrasonic vocalizations are produced by an edge-tone mechanism. Royal Society Open Science. 2017;4(11):170976. doi:doi:10.1098/rsos.170976

63. Håkansson J, Jiang W, Xue Q, et al. Aerodynamics and motor control of ultrasonic vocalizations for social communication in mice and rats. BMC Biology. 2022/01/07 2022;20(1):3. doi: 10.1186/s12915-021-01185-z

64. Nunez AA, Pomerantz SM, Bean NJ, Youngstrom TG. Effects of laryngeal denervation on ultrasound production and male sexual behavior in rodents. Physiol Behav. 1985;34(6):901 -905. doi:http://dx.doi.org/10.1016/0031-9384(85)90011-3

65. Riede T. Stereotypic laryngeal and respiratory motor patterns generate different call types in rat ultrasound vocalization. Journal of experimental zoology Part A, Ecological genetics and physiology. 2013;319(4):213-24. doi:10.1002/jez.1785

66. Sanders I, Weisz DJ, Yang BY, Fung K, Amirali A. The mechanism of ultrasound vocalization in the rat 2001:241.

67. Wetzel DM, Kelley DB, Campbell BA. Central control of ultrasonic vocalizations in neonatal rats: I. Brain stem motor nuclei. J Comp Physiol Psychol. 1980;94(4):596-605.

68. McGinnis MY, Vakulenko M. Characterization of 50-kHz ultrasonic vocalizations in male and female rats. Physiol Behav. 2003;80(1):81-88. doi: 10.1016/s0031-9384(03)00227-0

69. Marquis JM, Lettenberger SE, Kelm-Nelson CA. Early-onset Parkinsonian behaviors in female Pink1-/- rats. Behavioural Brain Research. 2019; (112175)doi:10.1016/j.bbr.2019.112175

70. Stevenson SA, Ciucci MR, Kelm-Nelson CA. Intervention changes acoustic peak frequency and mesolimbic neurochemistry in the Pink1-/- rat model of Parkinson disease. PLoS One. 2019;14(8): e0220734. doi:10.1371/journal.pone.0220734

71. Johnson RA, Kelm-Nelson CA, Ciucci MR. Changes to Ventilation, Vocalization, and Thermal Nociception in the Pink1-/- Rat Model of Parkinson's Disease. J Parkinsons Dis. 2020;10(2):489-504. doi :10.3233/jpd-191853

72. Pultorak JD, Kelm-Nelson CA, Holt LR, Blue KV, Ciucci MR, Johnson AM. Decreased approach behavior and nucleus accumbens immediate early gene expression in response to Parkinsonian ultrasonic vocalizations in rats. Social Neuroscience. 2016;11 (4):365-379. doi:10.1080/17470919.2015.1086434

73. Fox C, Ebersbach G, Ramig L, Sapir S. LSVT LOUD and LSVT BIG: Behavioral Treatment Programs for Speech and Body Movement in Parkinson Disease. Parkinson’s Disease. 2012/03 /15 2012;2012:391946. doi:10.1155/2012/391946

74. Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res. Feb 2008;51(1):S225-39. doi:10.1044/1 092-4388(2008/018)

75. Schmidt RA, Lee TD, Winstein C, Wulf G, Zelaznik HN. Motor control and learning: A behavioral emphasis. Human kinetics; 2018.

76. Hemsley B, Gregory C. People with Parkinson’s disease who succeed in the LSVT LOUD® treatment also report significant improvement in communication effectiveness, vocal disability, and communicative participation1. Evidence-Based Communication Assessment and Intervention. 2022/01/02 2022;16(1):17-23. doi:10. 1080/17489539.2022.2060041

77. Bryans LA, Palmer AD, Anderson S, Schindler J, Graville DJ. The impact of Lee Silverman Voice Treatment (LSVT LOUD®) on voice, communication, and participation: Findings from a prospective, longitudinal study. J Commun Disord. Jan-Feb 202 1;89:106031. doi:10.1016/j.jcomdis.2020.106031

78. Kelm-Nelson CA, Trevino MA, Ciucci MR. Quantitative Analysis of Catecholamines in the Pink1 -/- Rat Model of Early-onset Parkinson's Disease. Neuroscience. May 2018;379:126-141. doi:10.1016/j.neuroscience.2018.02.027

79. Lechner SA, Kelm-Nelson CA, Ciucci MR. Methylphenidate differentially affects the social ultrasonic vocalizations of wild-type and prodromal Parkinsonian rats. Behav Neurosci. Feb 2025;139 (1):1-9. doi:10.1037/bne0000610

80. Broadfoot CK, Lenell C, Kelm-Nelson CA, Ciucci MR. Effects of social isolation on 50-kHz ultrasonic vocalizations, affective state, cognition, and neurotransmitter concentrations in the ventral tegmental and locus coeruleus of adult rats. Behav Brain Res. Feb 2 2023;437:114157. doi:10.1016/j. bbr.2022.114157

81. Kelm-Nelson CA, Ciucci MR. Inhibition of signaling and metabolic pathways in the Pink1-/- rat model of early-onset Parkinsonism. 2019:

82. Hoffmeister JD, Kelm-Nelson CA, Ciucci MR. Quantification of brainstem norepinephrine relative to vocal impairment and anxiety in the Pink1-/- rat model of Parkinson disease. Behav Brain Res. Sep 24 2021;414:113514. doi:10.1016/ j.bbr.2021.113514

83. Kelm-Nelson CA, Gammie S. Gene expression within the periaqueductal gray is linked to vocal behavior and early-onset parkinsonism in Pink1 knockout rats. BMC Genomics. Sep 17 2020;2 1(1):625. doi:10.1186/s12864-020-07037-4

84. Barnett DGS, Lechner SA, Gammie SC, Kelm-Nelson CA. Thyroarytenoid Oxidative Metabolism and Synaptic Signaling Dysregulation in the Female Pink1-/- Rat. Laryngoscope. Jun 9 2023; doi:10.1002/lary.30768

85. Lechner SA, Welsch JM, Pahapill NK, Kaldenberg TAR, Regenbaum A, Kelm-Nelson CA. Predictors of prodromal Parkinson's disease in young adult Pink1-/- rats. Frontiers in behavioral neuroscience. 2022;16:867958. doi:10.3389/fnbeh .2022.867958

86. Lechner SA, Kletzien H, Gammie SC, Kelm-Nelson CA. Thyroarytenoid Muscle Gene Expression in a Rat Model of Early-Onset Parkinson's Disease. Laryngoscope. Dec 2021;131(12):E2874-e2879. doi:10.1002/lary.29661

87. Hirsch EC, Jenner P, Przedborski S. Pathogenesis of Parkinson's disease. Movement Disorders. 2013;28(1):24-30. doi:10.1002/mds.25032

88. Mu L, Sobotka S, Chen J, et al. Parkinson disease affects peripheral sensory nerves in the pharynx. Journal of Neuropathology and Experimental Neurology. 2013;72:614-623. doi:10.1097/NEN.0 b013e3182965886

89. Martirosyan A, Ansari R, Pestana F, et al. Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution. Molecular Neurodegeneration. 2024/01/20 2024;19(1):7. doi: 10.1186/s13024-023-00699-0

90. Ma SX, Lim SB. Single-Cell RNA Sequencing in Parkinson's Disease. Biomedicines. Apr 1 2021; 9(4)doi:10.3390/biomedicines9040368

91. Capani F, Quarracino C, Caccuri R, Sica RE. Astrocytes as the main players in primary degenerative disorders of the human central nervous system. Frontiers in Aging Neuroscience. 2016;8:45.

92. Halliday GM, Stevens CH. Glia: initiators and progressors of pathology in Parkinson's disease. Movement Disorders. 2011;26(1):6-17.

93. Smajić S, Prada-Medina CA, Landoulsi Z, et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain. 2021;145(3):964-978. doi:10.1093/ brain/awab446

94. Kouli A, Camacho M, Allinson K, Williams-Gray CH. Neuroinflammation and protein pathology in Parkinson's disease dementia. Acta Neuropathol Commun. Dec 3 2020;8(1):211. doi:10.1186/s4047 8-020-01083-5

95. Ouchi Y, Yagi S, Yokokura M, Sakamoto M. Neuroinflammation in the living brain of Parkinson's disease. Parkinsonism Relat Disord. Dec 2009;15 Suppl 3:S200-4. doi:10.1016/s1353-8020(09)70814-4

96. Zeng Z, Roussakis A-A, Lao-Kaim NP, Piccini P. Astrocytes in Parkinson's disease: from preclinical assays to in vivo imaging and therapeutic probes. Neurobiology of Aging. 2020/11/01/ 2020;95:264-270. doi:https://doi.org/10.1016/j.neurobiolaging.2020.07.012

97. Sun L, Shen R, Agnihotri SK, Chen Y, Huang Z, Büeler H. Lack of PINK1 alters glia innate immune responses and enhances inflammation-induced, nitric oxide-mediated neuron death. Sci Rep. Jan 10 2018;8(1):383. doi:10.1038/s41598-017-18786-w

98. Martirosyan A, Ansari R, Pestana F, et al. Unravelling cell type-specific responses to Parkinson's Disease at single cell resolution. Mol Neurodegener. Jan 20 2024;19(1):7. doi:10.1186/s13024-023-00699-0

99. Qian Z, Qin J, Lai Y, Zhang C, Zhang X. Large-Scale Integration of Single-Cell RNA-Seq Data Reveals Astrocyte Diversity and Transcriptomic Modules across Six Central Nervous System Disorders. Biomolecules. 2023;13(4):692.

100. Garcia P, Jürgens-Wemheuer W, Uriarte Huarte O, et al. Neurodegeneration and neuroinflammation are linked, but independent of alpha-synuclein inclusions, in a seeding/spreading mouse model of Parkinson's disease. Glia. May 2022;70(5):935-960. doi:10.1002/glia.24149

101. Na SJ, DiLella AG, Lis EV, et al. Molecular profiling of a 6-hydroxydopamine model of Parkinson's disease. Neurochem Res. May 2010;35 (5):761-72. doi:10.1007/s11064-010-0133-3

102. Li Z, Shu Y, Liu D, et al. Pink1/Parkin signaling mediates pineal mitochondrial autophagy dysfunction and its biological role in a comorbid rat model of depression and insomnia. Brain Research Bulletin. 2025/01/01/ 2025;220:111141. doi:https://doi.org/10.1016/j.brainresbull.2024.111141

103. Plotnikov A, Zehorai E, Procaccia S, Seger R. The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochim Biophys Acta. Sep 2011;1813(9):1619-33. doi:10.1016/j.bbamcr.2010.12.012

104. Saijo K, Winner B, Carson CT, et al. A Nurr1/CoREST pathway in microglia and astrocytes protects dopaminergic neurons from inflammation-induced death. Cell. Apr 3 2009;137(1):47-59. doi:10.1016/j.cell.2009.01.038

105. Pajares M, A IR, Manda G, Boscá L, Cuadrado A. Inflammation in Parkinson's Disease: Mechanisms and Therapeutic Implications. Cells. Jul 14 2020; 9(7)doi:10.3390/cells9071687

106. Park JS, Choe K, Lee HJ, Park TJ, Kim MO. Neuroprotective effects of osmotin in Parkinson’s disease-associated pathology via the AdipoR1/ MAPK/AMPK/mTOR signaling pathways. Journal of Biomedical Science. 2023/08/11 2023;30(1):66. doi:10.1186/s12929-023-00961-z

107. Narendra DP, Jin SM, Tanaka A, et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. Jan 26 2010;8(1):e10002 98. doi:10.1371/journal.pbio.1000298

108. Matsuda N, Sato S, Shiba K, et al. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J Cell Biol. Apr 19 2010;189(2):211-21. doi:10.1083/jcb.200910140

109. Clemente-Suárez VJ, Redondo-Flórez L, Beltrán-Velasco AI, et al. Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities. Biomedicines. Sep 7 2023;11(9)doi:10.3390/biomedicines11092488

110. Quinn PMJ, Moreira PI, Ambrósio AF, Alves CH. PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta Neuropathol Commun. Nov 9 2020;8(1):189. doi:10.1186/s40478-020-01062-w

111. Gautier CA, Kitada T, Shen J. Loss of PINK1 causes mitochondrial functional defects and increased sensitivity to oxidative stress. Proceedings of the National Academy of Sciences. 2008;105(32):113 64-11369. doi:doi:10.1073/pnas.0802076105

112. Herrero MT, Estrada C, Maatouk L, Vyas S. Inflammation in Parkinson's disease: role of glucocorticoids. Front Neuroanat. 2015;9:32. doi:1 0.3389/fnana.2015.00032

113. Sun L, Shen R, Agnihotri SK, Chen Y, Huang Z, Büeler H. Lack of PINK1 alters glia innate immune responses and enhances inflammation-induced, nitric oxide-mediated neuron death. Scientific Reports. 2018/01/10 2018;8(1):383. doi:10.1038/s41598-01 7-18786-w

114. Kim J, Byun JW, Choi I, et al. PINK1 Deficiency Enhances Inflammatory Cytokine Release from Acutely Prepared Brain Slices. Exp Neurobiol. Mar 2013;22(1):38-44. doi:10.5607/en.2013.22.1.38

115. Akundi RS, Huang Z, Eason J, et al. Increased mitochondrial calcium sensitivity and abnormal expression of innate immunity genes precede dopaminergic defects in Pink1-deficient mice. PLoS One. Jan 13 2011;6(1):e16038. doi:10.1371/ journal.pone.0016038

116. Berg D, Borghammer P, Fereshtehnejad S-M, et al. Prodromal Parkinson disease subtypes — key to understanding heterogeneity. Nature Reviews Neurology. 2021/06/01 2021;17(6):349-361. doi:1 0.1038/s41582-021-00486-9

117. Oliveira BdS, Toscano ECdB, Abreu LKS, et al. Nigrostriatal Inflammation Is Associated with Nonmotor Symptoms in an Experimental Model of Prodromal Parkinson’s Disease. Neuroscience. 202 4/06/21/ 2024;549:65-75. doi:https://doi.org/10.1016/j.neuroscience.2024.05.011

118. Terkelsen MH, Klaestrup IH, Hvingelby V, Lauritsen J, Pavese N, Romero-Ramos M. Neuroinflammation and immune changes in prodromal Parkinson’s disease and other synucleinopathies. Journal of Parkinson's disease. 2022;12(s1):S149-S163.

119. Tansey MG, Wallings RL, Houser MC, Herrick MK, Keating CE, Joers V. Inflammation and immune dysfunction in Parkinson disease. Nature Reviews Immunology. 2022/11/01 2022;22(11):657 -673. doi:10.1038/s41577-022-00684-6

120. Yacoubian TA, Fang Y-HD, Gerstenecker A, et al. Brain and Systemic Inflammation in De Novo Parkinson's Disease. Movement Disorders. 2023; 38(5):743-754. doi:https://doi.org/10.1002/mds.29363

121. Parrella E, Bellucci A, Porrini V, et al. NF-κB/c-Rel deficiency causes Parkinson's disease-like prodromal symptoms and progressive pathology in mice. Transl Neurodegener. 2019;8:16. doi:10.118 6/s40035-019-0154-z

122. Wrangel Cv, Schwabe K, John N, Krauss JK, Alam M. The rotenone-induced rat model of Parkinson's disease: Behavioral and electrophysiological findings. Behavioural Brain Research. 2015/02/15/ 2015;279:52-61. doi:https://doi.org/10.1016/j.bbr.2014.11.002

123. Cheng Y, Tong Q, Yuan Y, et al. α-Synuclein induces prodromal symptoms of Parkinson’s disease via activating TLR2/MyD88/NF-κB pathway in Schwann cells of vagus nerve in a rat model. Journal of Neuroinflammation. 2023/02/14 2023; 20(1):36. doi:10.1186/s12974-023-02720-1

124. Glass TJ, Kelm-Nelson CA, Szot JC, Lake JM, Connor NP, Ciucci MR. Functional characterization of extrinsic tongue muscles in the Pink1-/- rat model of Parkinson disease. PLoS One. 2020;15(10 ):e0240366-e0240366. doi:10.1371/journal.pone.0240366

125. Mazzotti AL, Coletti D. The Need for a Consensus on the Locution "Central Nuclei" in Striated Muscle Myopathies. Front Physiol. 2016;7:577. doi:10.3389/fphys.2016.00577

126. Hastings RL, Massopust RT, Haddix SG, Lee Yi, Thompson WJ. Exclusive vital labeling of myonuclei for studying myonuclear arrangement in mouse skeletal muscle tissue. Skeletal Muscle. 2020/05/07 2020;10(1):15. doi:10.1186/s13395-020-00233-6

127. Kelm-Nelson CA, Gammie S. Gene expression within the periaqueductal gray is linked to vocal behavior and early-onset parkinsonism in Pink1 knockout rats. BMC Genomics. 2020;21(1):625-625. doi:10.1186/s12864-020-07037-4

128. Lechner SA, Kletzien H, Gammie SC, Kelm-Nelson CA. Thyroarytenoid Muscle Gene Expression in a Rat Model of Early-Onset Parkinson's Disease. Laryngoscope. May 31 2021;doi:10.1002/lary.29661

129. Calsolaro V, Edison P. Neuroinflammation in Alzheimer's disease: Current evidence and future directions. Alzheimer's & dementia : the journal of the Alzheimer's Association. Jun 2016;12 (6):719-32. doi:10.1016/j.jalz.2016.02.010

130. Countryman S, Hicks J, Ramig LO, Smith ME. Supraglottal Hyperadduction in an Individual With Parkinson Disease. American Journal of Speech-Language Pathology. 1997;6(4):74-84. doi:doi:10.1 044/1058-0360.0604.74

131. Lechner SA, Barnett DGS, Gammie SC, Kelm-Nelson CA. Prodromal Parkinson disease signs are predicted by a whole-blood inflammatory transcriptional signature in young Pink1(-/-) rats. BMC Neurosci. Mar 4 2024;25(1):11. doi:10.1186/s12868-024-00857-0

132. Manfredsson FP, Burger C, Sullivan LF, Muzyczka N, Lewin AS, Mandel RJ. rAAV-mediated nigral human parkin over-expression partially ameliorates motor deficits via enhanced dopamine neurotransmission in a rat model of Parkinson's disease. Exp Neurol. Oct 2007;207(2):289-301. doi:10.1016/j.expneurol.2007.06.019

133. Liu B, Traini R, Killinger B, Schneider B, Moszczynska A. Overexpression of parkin in the rat nigrostriatal dopamine system protects against methamphetamine neurotoxicity. Exp Neurol. Sep 2013;247:359-72. doi:10.1016/j.expneurol.2013.01.001

134. Wadan AS, Shaaban AH, El-Sadek MZ, et al. Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature. Naunyn Schmiedebergs Arch Pharmacol. Sep 2025;398(9) :11357-11386. doi:10.1007/s00210-025-04014-0