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Defining essential charged residues in fibril formation of a lysosomal derived N-terminal α-synuclein truncation

8 months ago
N- and C-terminal α-synuclein (α-syn) truncations are prevalent in Parkinson's disease. Effects of the N- and C-terminal residues on α-syn aggregation and fibril propagation are distinct, where the N-terminus dictates fibril structure. Here, the majority of α-syn truncations are assigned by intact mass spectrometry to lysosomal activity. To delineate essential charged residues in fibril formation, we selected an N-terminal truncation (66-140) that is generated solely from soluble α-syn by...
Ryan P McGlinchey

LinAge2: providing actionable insights and benchmarking with epigenetic clocks

8 months ago
Biological aging is marked by a decline in resilience at the cellular and systemic levels, driving an exponential increase in mortality risk. Here, we evaluate several clinical and epigenetic clocks for their ability to predict mortality, demonstrating that clocks trained on survival and functional aging outperform those trained on chronological age. We present an enhanced clinical clock that predicts mortality more accurately and provides actionable insights for guiding personalized...
Sheng Fong

Loss of intracellular ATP affects axoplasmic viscosity and pathological protein aggregation in mammalian neurons

8 months ago
Neurodegenerative diseases display synaptic deficits, mitochondrial defects, and protein aggregation. We show that intracellular adenosine triphosphate (ATP) regulates axoplasmic viscosity and protein aggregation in mammalian neurons. Decreased intracellular ATP upon mitochondrial inhibition leads to axoterminal cytosol, synaptic vesicles, and active zone component condensation, modulating the functional organization of mouse glutamatergic synapses. Proteins involved in the pathogenesis of...
Laurent Guillaud

Genetics- and age-driven neuroimmune and disc changes underscore herniation susceptibility and pain-associated behaviors in SM/J mice

8 months ago
There are no appropriate mouse models to study the pathophysiology of spontaneous disc herniations in a wild-type setting. SM/J mice, a poor healer inbred strain, presented a high incidence of age-associated lumbar disc herniations with neurovascular innervations. Transcriptomic comparisons of the SM/J annulus fibrosus with human tissues showed shared pathways related to immune cell activation and inflammation. Notably, aged SM/J mice showed increased pain sensitization and neuroinflammation...
Emanuel J Novais