Associate Professor Simone Engelender
Neurodegenerative diseases, especially Alzheimer’s (AD) and Parkinson’s disease (PD), are highly prevalent among the elderly population and therefore are likely to be closely associated with aging. These diseases are characterized by the accumulation of insoluble proteins in the brain that culminate into neuronal dysfunction and eventual neuronal death. To date, there is no treatment that can prevent or halt their progression. Even though AD and PD are considered to represent different entities, they share several features, including the accumulation of ubiquitinated inclusions as well as the co-accumulation of a-synuclein, Abeta and Tau proteins. For instance, while extracellular amyloid-β (Aβ) plaques and Tau neurofibrillary tangles are the main lesions in AD brains, the widespread accumulation of intracellular a-synuclein inclusions (termed Lewy bodies) as well as the co-aggregation of a-synuclein at the periphery of Aβ plaques are frequently observed. On the other hand, while PD is characterized by the accumulation of a-synuclein into Lewy bodies, Tau increases the aggregation of a-synuclein and represents a common risk factor for sporadic PD.
Our laboratory has been studying the molecular mechanisms responsible for the accumulation of proteins in neurodegenerative diseases, especially a-synuclein, and how dysfunction of intracellular proteolytic systems are involved in this process. Various studies have shown that the proteasome and autophagy functions are compromised in PD and AD. We have shown that a-synuclein is processed by different degradation systems, including autophagy and the ubiquitin proteasome system. However, the mechanisms that control a-synuclein degradation had remained elusive. We recently found that the E3 ubiquitin-ligase SIAH monoubiquitinates a-synuclein leading to its degradation by the proteasome. We also observed that conditions favouring deubiquitination lead to the degradation of a-synuclein at a slower pace by autophagy, indicating that the levels of monoubiquitination are important to determining the fate and the steady-state levels of a-synuclein. In conditions that mimic proteolysis inhibition, we observed that the accumulation of monoubiquitinated a-synuclein species leads to the formation of toxic a-synuclein inclusions, suggesting that the accumulation of monoubiquitinated a-synuclein may trigger the death of neurons in neurodegenerative conditions.
We propose to investigate further the mechanisms that modulate the degradation and accumulation of a-synuclein as well as Tau and Aβ that accumulate in AD.