Interaction of Brain-Expressed Ubiquilins in Normal Function and Disease.
The ubiquitin-like proteins UBQLNs1, 2, and 4, which are expressed in brain tissue, are implicated in various neurodegenerative disorders, including ALS/FTD, Huntington's disease, and synucleinopathies. Mutations in UBQLN2 and UBQLN4 lead to pathogenic aggregation, particularly in familial ALS/FTD cases. These proteins are essential for maintaining protein homeostasis and clearing damaged or misfolded proteins. Their inactivation results in a range of neurological symptoms and abnormal cellular proliferation. Multiple studies suggest that a crucial aspect of these proteins' function is liquid phase separation within the cell, which can enhance their functionality but also contribute to abnormal aggregation. Our research focuses on gaining molecular insights into the role of phase separation (condensation) of brain-expressed ubiquilins in both normal and disease conditions.
SARS-CoV-2-Induced Proteopathic Protein Aggregation in AD/ADRD.
A growing concern has emerged regarding the potential for SARS-CoV-2 infection to induce neuropathological conditions resembling Alzheimer's disease (AD). Recent studies have shown a higher incidence of dementia in the elderly population who contracted the virus. While the exact mechanisms through which the virus might contribute to neurodegeneration remain unclear, there is significant evidence suggesting that viral infections can directly cause protein aggregation. Building on previous reports indicating that viral infections can trigger pathological protein aggregation—including those of α-synuclein (α-syn), tau, and TDP-43—we observed increased aggregation of TDP-43 and tau proteins in neurons infected by the virus. These findings led us to hypothesize that viral particles and proteins may enhance the aggregation of proteopathic proteins seen in AD and related dementias (ADRD) by promoting toxic protein aggregation through cross-protein interactions.
Molecular Studies of α-Synuclein Aggregation in Neurodegenerative Disorders.
Our research spans a wide range of studies focusing on α-synuclein aggregation and its impacts on neurodegenerative diseases. While α-synuclein has been implicated in various diseases, it remains unclear how the aggregation of this single protein can lead to multiple distinct disease phenotypes and clinical outcomes. To address these questions, we study the structural heterogeneity of α-synuclein inclusions in Parkinson’s disease (PD), Dementia with Lewy bodies (DLB), Alzheimer’s disease with Lewy bodies, and multiple system atrophy (MSA), and relate these structures to their specific disease phenotypes. The goal is to connect these unique structural features to the specific disease phenotypes they present and explain the disease origin. We utilize a multifaceted approach encompassing computational, biophysical, and cellular methodologies to decipher the molecular mechanisms governing the aggregation and spread of α-synuclein.