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Brain of a PD patient and brain of a healthy control

TDP-43 and Me: the Neurodegenerative Impact of Gene Misplacement in Parkinsonism

Practice and Progress in Neurology

Since 2006 when the link between amyotrophic lateral sclerosis (ALS), frontotemporal degeneration and TDP-43 mutations was demonstrated by Arai et al., it has remained a focus in neurological academia. This is for good reason; the research boom around the role of TDP-43 in neurodegeneration has elucidated links between TDP-43, parkinsonism and frontotemporal dementia (FTD).

 

The link between point mutations, deletions and loss of gene function in PRKN has long been established, but has yet to lead to the development of a targeted therapeutic treatment. PRKN is involved in the tagging of excess or faulty proteins with ubiquitin, which leads to degradation of the proteins in the ubiquitin/proteasome system (UPS)- a system characterised in medical neurology by its potential to cause serious neurological disorders. This places parkinsonism in a domain of neurodegenerative disorders sharing a common root in UPS dysfunction, including Alzheimer’s Disease, multiple sclerosis and Huntington’s Disease. 

Panda et al. (2022) demonstrated how the dysfunction of the UPS due to PRKN aberration inhibits the breakdown of the damaging TDP-43 aggregates which develop in human brains in response to mutation or stress. In healthy people, autophagic granules would attack and kill off these TDP-43 aggregates as an end result of the UPS (Riku et al. 2014), but due to aberrations in PRKN the UPS is inhibited in those afflicted with parkinsonism, causing neurodegeneration. The discovery of how TDP-43 and parkinsonism are linked could lead to the development of a treatment mimicking the organic catalyst of the TDP-43 aggregate breakdown to replicate UPS, reducing TDP-43 aggregate volume and by proxy, inhibiting neurodegeneration.

 

In 2007, research by Esper et al. catalysed recognition of drug-induced Parkinsonism as severely underdiagnosed, with evidence proving even neurologists fail to effectively remember which medications cause parkinsonism. Fast halting of the inciting agent is necessary for the reversal of all parkinsonism symptoms, but in some patients, cognitive symptoms may persist for a time after the medication is stopped. In response to the novel discoveries of Panda et al. (2022), it is likely due to the aggregation of TDP-43. Another possibility is that permanent cognitive symptoms after inciting agent cessation in DIP may be due to large TDP-43 aggregates unable to be destroyed by the UPS. Further research will demonstrate whether TDP-43 aggregates become more resistant to UPS or autophagy through the progression of DIP, whether due to size or other extraneous factors.

 

The implications of such a promising lead in neurotherapeutics for refractory parkinsonism cannot be understated. Surgical therapies have long since remained the industry standard in treating refractory parkinsonism, though this option remains prone to risk since many of those afflicted with parkinsonism are elderly, with drug-induced parkinsonism from treatment with antipsychotics, calcium channel blockers or other medications always heightening the number of the geriatric population requiring care for parkinsonism (Shin et al. 2012). Furthermore, the adequate treatment of those with parkinsonism in their youth could inhibit their progression to a refractory disease state in old age. Overall, the future looks very promising for those around the world suffering from all different forms of parkinsonism.

By Aimee Wilson

The pathway by which substrates are destroyed by via the Parkin-mediated UPS system
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