Journal Article

DZNE-2026-00621

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png VAPB confers selective neuroprotection by driving autophagic degradation of pathogenic aggregates in ALS.

Tripathi, P. ; Guo, H. ; Yamoah, A. ; Mathur, R. ; Doukas, P. ; Dreser, A. ; Jesse, C. M. ; Aronica, E. ; Hermann, A.DZNE* ; Steinbusch, H. ; Brook, G. A. ; Weis, J. ; Goswami, A.

2026
Biomed Central London

This record in other databases:    

Please use a persistent id in citations: doi:10.1186/s40478-026-02298-8

Abstract: During the progression of amyotrophic lateral sclerosis (ALS), only specific motor neurons (MNs) preferentially deteriorate, while others are spared until the disease reaches its end stage. Resilient MNs possess several protective factors, yet the precise molecular mechanism(s) underlying selective neuronal vulnerability remains poorly understood. Vesicle-associated membrane protein (VAMP)-binding protein B (VAPB) is an endoplasmic reticulum (ER) protein involved in protein quality control (PQC) mechanisms, including unfolded protein response (UPR) as well as autophagy. A dominantly inherited P56S mutation in the VAPB gene has been linked to ALS8, atypical ALS, and late-onset spinal muscular atrophy (SMA). The P56S VAPB mutation causes ER-associated inclusions, disorganization, and ER stress, contributing to MN degeneration through toxic gain and loss of function. Over-expression of VAPB protein confers neuroprotection in a mouse model of ALS, and increased levels of neuronal VAPB inversely correlate with the absence of pathological aggregates. We hypothesize that VAPB is crucial for motor neuron survival by promoting autophagic degradation of ALS-associated aggregates, while lack of VAPB confers neuronal vulnerability. We analyzed the brain and spinal cord from sporadic (s) and familial (f) ALS patients, comparing patterns of VAPB immunoreactivity using immunohistochemistry, complemented by Western and dot blot analysis. Pathophysiological insights from these studies were further explored using cell culture models, including MNs derived from induced pluripotent stem cells (iPSCs). Consistent with our hypothesis we observed that MNs/neurons resistant to ALS exhibited elevated levels of VAPB and were devoid of pathogenic aggregates. Similarly, ALS-resistant oculomotor neurons showed increased VAPB immunoreactivity compared to normal controls. VAPB was often found to be sequestered within toxic aggregates alongside autophagy-related proteins in the lumbar spinal cord MNs. Notably, a compensatory increase in VAPB immunoreactivity was observed at the C-bouton synapse, suggesting a potential alternative mechanism of neuroprotection. Supporting these findings, in vitro experiments indicated that VAPB overexpression promoted autophagy and assisted in clearing ALS-associated RNA-binding protein aggregates. In summary, VAPB promotes selective neuronal survival by facilitating the autophagic clearance of toxic aggregates. Abnormal VAPB accumulations likely disrupt these neuroprotective processes.

Keyword(s): Amyotrophic Lateral Sclerosis: pathology (MeSH) ; Amyotrophic Lateral Sclerosis: metabolism (MeSH) ; Amyotrophic Lateral Sclerosis: genetics (MeSH) ; Autophagy: physiology (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Vesicular Transport Proteins: metabolism (MeSH) ; Vesicular Transport Proteins: genetics (MeSH) ; Motor Neurons: metabolism (MeSH) ; Motor Neurons: pathology (MeSH) ; Spinal Cord: pathology (MeSH) ; Spinal Cord: metabolism (MeSH) ; Neuroprotection: physiology (MeSH) ; Female (MeSH) ; Mice (MeSH) ; Male (MeSH) ; Brain: pathology (MeSH) ; Brain: metabolism (MeSH) ; Mice, Transgenic (MeSH) ; Protein Aggregation, Pathological: metabolism (MeSH) ; Protein Aggregation, Pathological: pathology (MeSH) ; ALS8 ; Autophagy ; RBPs ; Selective MN vulnerability ; VAPB ; Vesicular Transport Proteins ; VAPB protein, human ; VAPB protein, mouse

---

Contributing Institute(s):

1. Translational Neurodegeneration (AG Hermann)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

---

Database coverage:
; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Ebsco Academic Search ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

---