Myla Sykes

Introduction: PD is caused by alpha-synuclein aggregates in the sub-cortical basal ganglia. Cardinal symptoms of PD include a triad of pill-rolling/resting tremor, bradykinesia, and cogwheel rigidity^1,2. In addition, sleep disorders often manifest early in the progression of the disease. mRGCs convey light signals from the retina to the brain for non-image forming functions including circadian rhythm regulation, melatonin production, and pupillary light reflex³. mRGC degeneration is a potential cause for sleep disruption in PD patients, but the mechanism behind the cell loss is largely unknown⁴. This study proposes alpha-synuclein aggregation in the retina as the mechanism of mRGC loss and sleep disruption.  Methods: Many sources were reviewed to connect alpha-synuclein aggregates to mRGC loss and sleep disruption in PD patients. One reference stained retinas for alpha-synuclein aggregates co-localized with mRGCs. The purpose was to determine if these aggregates are present in the mRGC layer of the retina⁵. A subsequent study induced alpha-synuclein aggregates intravitreally into mice using an adeno-associated viral (AAV) vector. AAV-infected retinas were analyzed by immunohistochemical staining for dopamine (DA) neurons using tyrosine hydroxylase (TH) to quantify DA neuron degradation with alpha-synuclein aggregation⁶. Next, a study stained retinas for mRGCs and DA neurons to correlate loss of DA neurons to loss of mRGCs⁷. Lastly, a study measured pupillary light reflex in PD and non-PD patients, and measured the quality of sleep in the subjects for the purpose of relating mRGC loss to sleep dysfunction⁸. Results: Alpha-synuclein is present in the retinas of PD patients. It was localized in the cell bodies, dendrites, and axons of mRGCs. Alpha-synuclein was not detected in the retinas of non-PD control patients⁵. When alpha-synuclein aggregation is induced in the retinas of mice there is a decrease in number of DA neurons⁶. In the retinas of PD patients, there are 35% fewer DA neurons in contact with mRGCs. This decreased innervation correlates with decreased morphology of mRGCs in PD patients⁷. In PD patients there is a decreased pupillary light reflex which implies decreased number of mRGCs. The same subjects reported significantly lower quality of sleep using a sleep diary. This finding suggests decreased mRGCs may contribute to sleep disorders⁸. Conclusion: Collectively, these studies correlate alpha-synuclein aggregation with a decrease in number of DA neurons resulting in mRGCs losing synaptic inputs and consequently resulting in alterations in mRGC cellular morphology^5,6,7. Multiple other studies then connect the decreased number and morphology of mRGCs to the presence of sleep disorders⁸. Future work should focus on therapies targeted towards decreasing alpha-synuclein aggregates in the retina to improve PD patient’s quality of sleep.

1. Jankovic J, Tan EK. Parkinson’s disease: etiopathogenesis and treatment. J Neurol Neurosurg Psychiatry. 2020;91(8):795-808. doi:10.1136/jnnp-2019-322338
2. Colwell CS. Defining circadian disruption in neurodegenerative disorders. J Clin Invest. 2021;131(19):e148288. doi:10.1172/JCI148288
3. Do MTH. Melanopsin and the Intrinsically Photosensitive Retinal Ganglion Cells: Biophysics to Behavior. Neuron. 2019;104(2):205-226. doi:10.1016/j.neuron.2019.07.016
4. Ortuño-Lizarán I, Esquiva G, Beach TG, et al. Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson’s disease. Acta Neuropathol Commun. 2018;6(1):90. Published 2018 Sep 10. doi:10.1186/s40478-018-0596-z
5. Ortuño-Lizarán I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N. Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord. 2018;33(8):1315-1324. doi:10.1002/mds.27392
6. Marrocco E, Indrieri A, Esposito F, et al. α-synuclein overexpression in the retina leads to vision impairment and degeneration of dopaminergic amacrine cells. Sci Rep. 2020;10(1):9619. Published 2020 Jun 15. doi:10.1038/s41598-020-66497-6
7. Ortuño-Lizarán I, Sánchez-Sáez X, Lax P, et al. Dopaminergic Retinal Cell Loss and Visual Dysfunction in Parkinson Disease. Ann Neurol. 2020;88(5):893-906. doi:10.1002/ana.25897
8. Feigl B, Dumpala S, Kerr GK, Zele AJ. Melanopsin Cell Dysfunction is Involved in Sleep Disruption in Parkinson’s Disease. J Parkinsons Dis. 2020;10(4):1467-1476. doi:10.3233/JPD-202178