Biology subjects

Ndayambaje, I. S.

Publications and source records attributed to Ndayambaje, I. S..

4 recordsLinked to original sources

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↗

bioRxiv2026

Statins and genetic inhibition of the mevalonate pathway activate an ATF3-STMN2 regenerative program

Loss of neuronal regenerative capacity is a common feature of neurodegenerative disease and axonal injury, yet the transcriptional programs governing this state remain poorly defined. Stathmin-2 (STMN2), a tubulin-binding protein essential for axon maintenance and repair, is profoundly depleted following loss of nuclear TDP-43 in neurodegenerative disease. Here, we identify statins as potent inducers of STMN2 expression. Pharmacological and genetic suppression of the mevalonate pathway, and subsequent prevention of protein geranylgeranylation, restored STMN2 levels in TDP-43 deficient cells and promoted neurite growth. STMN2 induction was abrogated when using a statin analogue unable to interact with HMG-CoA reductase, and through co-administration of mevalonate or geranylgeranyl diphosphate substrates. RNA-seq revealed that statins induce a coordinated pro-regenerative transcriptional response, including activation of the AP-1 transcription factor complex gene, ATF3. Loss of ATF3 attenuated STMN2 induction in vitro, and diminished injury-induced Stmn2 upregulation in spinal motor neurons in vivo. These results demonstrate statins as modulators of ATF3 and STMN2 expression and highlight their therapeutic potential in neurodegenerative disease.

neuroscience↗

bioRxiv2022

Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation

The human mRNA most affected by TDP-43 loss-of-function is transcribed from the STMN2 gene and encodes stathmin-2 (also known as SCG10), whose loss is a neurodegenerative disease hallmark. Here using multiple in vivo approaches, including transient antisense oligonucleotide (ASO)-mediated suppression, chronic shRNA-mediated depletion in aging mice, and germline deletion, we establish stathmin-2 to be essential for acquisition and maintenance of neurofilament-dependent structuring of axoplasm critical for maintaining diameter and conduction velocity of large-myelinated axons. Sustained stathmin-2 loss from an otherwise mature adult nervous system is demonstrated over a time course of eight months to initiate and drive motor neuron disease that includes 1) shrinkage in inter-neurofilament spacing that is required to produce a three-dimensional space filling array that defines axonal caliber, 2) collapse of mature axonal caliber with tearing of outer myelin layers, 3) reduced conduction velocity, 4) progressive motor and sensory deficits (including reduction of the pain transducing neuropeptide CGRP), and 5) muscle denervation. Demonstration that chronic stathmin-2 reduction is itself sufficient to trigger motor neuron disease reinforces restoration of stathmin-2 as an attractive therapeutic approach for TDP-43-dependent neurodegeneration, including the fatal adult motor neuron disease ALS.

cell biology↗

bioRxiv2022

iPSC Motor Neurons with Familial ALS Mutations Capture Gene Expression Changes in Postmortem Sporadic ALS Motor Neurons

Motor neuron degeneration, the defining feature of ALS, is a primary example of cell-type specificity in neurodegenerative diseases. Using isogenic pairs of iPSCs harboring different familial ALS mutations, we assess the capacity of iPSC-derived spinal motor neurons, sensory neurons, astrocytes, and superficial cortical neurons to capture disease features including transcriptional and splicing dysregulation observed in human post-mortem neurons. At surprisingly early time points, differentially regulated genes in iPSC-derived spinal motor neurons, but not other cell types, overlap with one-third of the differentially regulated genes in laser-dissected motor neurons from postmortem spinal cords. The extent of dysregulation correlates well between iPSC-derived and bona fide spinal motor neurons. In iPSC-derived spinal motor neurons, but not other derived cell types, we detect downregulation of genes affected by TDP-43-dependent aberrant splicing. This reduction takes place exclusively within genotypes known to involve TDP-43 pathology and occurs without evidence of TDP-43 mislocalization or protein level alteration.

neuroscience↗