Cook, E. E. | Search bioRxiv

bioRxiv2026

Neurodegeneration risk variants promote lysosomal TMEM106B fibrilaccumulation

Variants in TMEM106B and GRN, which encode lysosomal proteins, interact through unknown mechanisms to increase the risk of age-related cognitive decline and neurodegeneration. Here, we show that these variants converge on a single molecular intermediate: the cleaved intra-lysosomal fibril core of TMEM106B, a precursor to amyloid fibrils that accumulate in the aging brain. A protein-coding TMEM106B risk variant (p.T185) drives fibril core accumulation by impairing its degradation and GRN risk variants amplify this effect. Mice over-expressing the fibril core develop hallmarks of neurodegeneration, and cryo-electron tomography reveals intra-lysosomal fibrils in cultured neurons, mice, and diseased human brain. In GRN-mutation carriers, in whom fibril burden is greatest, fibrils extrude through ruptured lysosomal membranes. These findings identify intra-lysosomal TMEM106B fibrillization as a convergent neurodegeneration mechanism and potential therapeutic target.

cell biology↗

bioRxiv2022

Spontaneous behavioural recovery following stroke relates to the integrity of sensory and association cortices

Stroke is a devastating disease that results in neurological deficits and represents a leading cause of death and disability worldwide. Following a stroke, there is a degree of spontaneous recovery of function, the neural basis of which is of great interest among clinicians in their efforts to reduce disability following stroke and enhance rehabilitation. Conventionally, work on spontaneous recovery has tended to focus on the neural reorganization of motor cortical regions, with comparably little attention being paid to changes in non-motor regions and how these relate to recovery. Here we show, using structural neuroimaging in a macaque stroke model and by exploiting individual differences in spontaneous behavioural recovery, that the preservation of regions in the sensory and association cortices predict animal recovery. To characterize recovery, we performed a clustering analysis using Non-Human Primate Stroke Scale (NHPSS) scores and identified a good versus poor recovery group. By comparing the preservation of brain volumes in the two groups, we found that brain areas in integrity of brain areas in parietal, temporal and somatosensory cortex were associated with better recovery. In addition, a decoding approach performed across all subjects revealed that the preservation of specific brain regions in the parietal, somatosensory and medial frontal cortex predicted recovery. Together, these findings highlight the importance of the sensory and association regions in spontaneous behavioural recovery, supporting the notion that the sensory retraining of impairments following stroke is critical to recovery and motor function.

neuroscience↗