Figuring out what happens first in Parkinson’s disease is a difficult task. People are not usually diagnosed until they experience motor symptoms, at which point 70-80% of their nigrostriatal dopamine neurons have already died. This makes it hard to trace the sequence of events that leads to neuronal degeneration.

For many years, the predominant view of Parkinson’s disease pathology was that neuronal death was caused by the formation of alpha synuclein-rich aggregates known as Lewy bodies and Lewy neurites. These aggregates were thought to be toxic to cells—when enough of them accumulate, the cells die.

This view is supported by the presence of Lewy bodies in the substantia nigra and locus coeruleus, brain areas with prominent neurodegeneration in Parkinson’s disease.¹ Indeed, Lewy pathology is a hallmark of Parkinson’s disease, and its progression from the dorsal motor nucleus of the vagus to the cerebral cortex forms the basis for proposed disease stages.²

 

However, Lewy bodies are not always associated with degenerating neurons in the substantia nigra, and vice versa.³ This and other findings led to suggestions that Lewy pathology may be a consequence rather than a cause of Parkinson’s disease, or even a protective mechanism.⁴ The jury is still out on the role of Lewy bodies and neurites.⁵

Synaptic dysfunction in early Parkinson’s disease

If Lewy bodies and neurites don’t cause Parkinson’s disease, then what does? One candidate is synaptic dysfunction, also known as synaptopathy. Studies in human tissue and cells have found impaired trafficking of synaptic vesicles early in Parkinson’s disease.⁶ People with Parkinson’s disease also show greater loss of striatal dopaminergic neurotransmission and neurites than nigrostriatal dopamine neurons at the time of diagnosis.⁷

But, how can we determine whether synaptic dysfunction precedes cell death? One way this can be addressed is in animal models. In fact, a variety of animal models of Parkinson’s disease do show synaptic dysfunction before motor dysfunction and/or cell death.⁸ Findings include defects in exocytosis and endocytosis, altered intracellular trafficking, loss of synaptic plasticity in corticostriatal pathways, and deficits in ion channel function.^8,9

What causes the synaptic dysfunction?

Taking another step back, if synaptic dysfunction is an early event in Parkinson’s disease, what causes it? One possibility is the accumulation of small alpha synuclein aggregates at the presynapse. Numbers of these aggregates at the presynapse are 1 to 2 orders of magnitude higher than in Lewy bodies.¹⁰ Alpha synuclein plays multiple roles in synaptic vesicle release and recycling, as well as in the trafficking of transporters and receptors.¹¹ If alpha synuclein misfolds and aggregates, it may be unable to perform its normal functions, leading to synaptic deficits.¹² This idea is supported by degeneration of nigrostriatal dopamine neurons in animal models that lack alpha synuclein.¹² Thus, the problem with alpha synuclein in Parkinson’s disease may not be a toxic gain of function, but a loss of normal function—a 180° turn in our thinking about this protein in Parkinson’s disease.

These ideas are intriguing, but do they fit with the overexpression of alpha synuclein in people with multiplication of the SNCA gene? Is synaptic dysfunction in Parkinson’s disease the chicken or the egg? Do neurons die because their synapses are dysfunctional or for some other reason? I’d appreciate your input and thoughts—please leave a comment.

References

1. Beyer K, Domingo-Sabat M, Ariza A. Molecular pathology of Lewy body diseases. Int J Mol Sci. Mar 2009;10(3):724-745.
2. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K. Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res. Oct 2004;318(1):121-134.
3. Tompkins MM, Hill WD. Contribution of somal Lewy bodies to neuronal death. Brain Res. Nov 14 1997;775(1-2):24-29.
4. Olanow CW, Perl DP, DeMartino GN, McNaught KS. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol. Aug 2004;3(8):496-503.
5. Sian-Hulsmann J, Monoranu C, Strobel S, Riederer P. Lewy Bodies: A Spectator or Salient Killer? CNS Neurol Disord Drug Targets. 2015;14(7):947-955.
6. Hunn BH, Cragg SJ, Bolam JP, Spillantini MG, Wade-Martins R. Impaired intracellular trafficking defines early Parkinson’s disease. Trends Neurosci. Mar 2015;38(3):178-188.
7. Nikolaus S, Antke C, Muller HW. In vivo imaging of synaptic function in the central nervous system: I. Movement disorders and dementia. Behav Brain Res. Dec 1 2009;204(1):1-31.
8. Schirinzi T, Madeo G, Martella G, et al. Early synaptic dysfunction in Parkinson’s disease: Insights from animal models. Mov Disord. Jun 2016;31(6):802-813.
9. Branch SY, Chen C, Sharma R, Lechleiter JD, Li S, Beckstead MJ. Dopaminergic Neurons Exhibit an Age-Dependent Decline in Electrophysiological Parameters in the MitoPark Mouse Model of Parkinson’s Disease. J Neurosci. Apr 6 2016;36(14):4026-4037.
10. Schulz-Schaeffer WJ. The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson’s disease and Parkinson’s disease dementia. Acta Neuropathol. Aug 2010;120(2):131-143.
11. Yu S, Chan P. Role of alpha-synuclein in neurodegeneration: implications for the pathogenesis of Parkinson’s disease. Essays Biochem. 2014;56:125-135.
12. Collier TJ, Redmond DE, Jr., Steece-Collier K, Lipton JW, Manfredsson FP. Is Alpha-Synuclein Loss-of-Function a Contributor to Parkinsonian Pathology? Evidence from Non-human Primates. Front Neurosci. 2016;10:12.

 

Thanks to Pixabay for many of the graphics on this website: https://pixabay.com/en/