Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world – only Alzheimer’s dementia is more common. Yet the cause of the disease has eluded scientists for years – stretching back to 1817, when it was described as the ‘Shaking Palsy’ by James Parkinson. Whilst we can treat some of the symptoms well, our management of the disease is limited by what we don’t know.
Research into PD has shown that other diseases, such as Lewy-Body dementia and multiple system atrophy (MSA), have shared qualities and these diseases share a common mechanism of neurodegeneration.
Early on in the disease, it is often difficult to clinically differentiate between PD and multiple system atrophy. Both diseases primarily affect the motor system and cause a similar range of debilitating symptoms making it harder to diagnose accurately. Whilst PD broadly affects the motor system; multi-system atrophy, like the name implies, damages other areas including the autonomic nervous system and causes cognitive impairment. As such, it is vital to identify early and treat each disease accordingly and separately.
They both also have a different clinical presentation. While both diseases show features of “Parkinsonism” i.e. rigidity, tremor and bradykinesia, Parkinson’s disease tends to have a unilateral 2-5 Hz pill rolling tremor, stooped posture and a shuffling gait. Multi-system atrophy tends to additionally cause cerebellar signs (DANISH) with a predominance of autonomic symptoms, such as postural hypotension.
It is because of these differences in clinical presentation (which require different symptomatic treatments) and the underlying pathophysiology, that there is an importance in developing alternative methods to diagnose the two diseases. It has been suggested that the α-synuclein protein which causes the damage in both diseases may hold the key to differentiate the disease early on. Whilst this protein is made in the healthy population, in a specific subset of diseases known as synucleinopathies (including PD, MSA and Lewy Body dementia) the protein is folded incorrectly and aggregates abnormally. These aggregates are the primary cause of neurodegeneration as they are toxic to cells (cytotoxic).
This study suggests that whilst α-synuclein may be aggregated in both diseases, the manner in which this happens is very different.
To investigate this, the researchers used protein misfolding cyclic amplification (PMCA), a technique that mimics the pathological process of α-synuclein misfolding through cyclic agitation of cerebrospinal fluid samples from patients with the disease. This allows the amplification of the sample and thorough analysis of samples. Using samples from normal healthy subjects and patients with PD and MSA, the researchers showed significant differences between samples from PD and MSA. Moreover, they demonstrated that the same α-synuclein in both diseases was not only structurally different but have different levels of cytotoxicity.
The study did have some important limitations to consider. The PD patients had been diagnosed with the disease for more time on average (8 years) than those with MSA (4 years) – there is a chance that the α-synuclein may have time dependent changes as well as disease dependent changes. There also may be a chance that dopamine treatment, which is common in PD, may affect how α-synuclein aggregates: potentially confounding the results. Also, this study only looked retrospectively at patients with confirmed diagnoses, whether or not this method holds up in patients without a diagnosis remains to be seen.
On the whole, these results may pave the way for the development of biochemical tests to more easily differentiate different disorders that involve α-synuclein, which could be a game changes for patients with either of these conditions.
Shahnawaz, M. et al. Discriminating α-synuclein strains in Parkinson’s disease and multiple system atrophy. Nature 578, 273–277 (2020).
Image references: https://pubs.asha.org/doi/10.1044/2019_JSLHR-S-18-0425 https://www.nature.com/articles/d41586-020-00131-3 Front cover https://www.techexplorist.com/alzheimers-may-linked-deficient-brain-cells-spreading-disease/10623/
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