Biology subjects

Pant, D. C.

Publications and source records attributed to Pant, D. C..

3 recordsLinked to original sources

bioRxiv2025

Targeted plasma proteomics uncover novel proteins associated with KIF5A-linked SPG10 and ALS spectrum disorders

KIF5A (Kinesin family member 5A) is a motor protein that functions as a key component of the axonal transport machinery. Variants in KIF5A are linked to several neurodegenerative diseases, mainly spastic paraplegia type 10 (SPG10), Charcot-Marie-Tooth disease type 2 (CMT2), and amyotrophic lateral sclerosis (ALS). These diseases share motor neuron involvement but vary significantly in clinical presentation, severity, and progression. KIF5A variants are mainly categorized into N-terminal variants associated with SPG10/CMT2 and C-terminal variants linked to ALS. This study utilized a novel multiplex NULISA targeted platform to analyze plasma proteome from KIF5A-linked SPG10, ALS patients and compared to healthy controls. Our results revealed distinct proteomic signatures, with significant alterations in proteins related to synaptic function, and inflammation. Notably, neurofilament light polypeptide, a biomarker for neurodegenerative diseases, was elevated in KIF5A ALS but not in SPG10 patients. Moreover, these findings can now be taken forward to gain mechanistic understanding of axonopathies linking to N-vs C-terminal KIF5A variants affecting both central and peripheral nervous systems.

neuroscience↗

bioRxiv2025

Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice

Mutations in the human SPTLC1 gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked SPTLC1 mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function in vivo and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human SPTLC1, we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine Sptlc1 locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that Sptlc1 {Delta}Exon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.

neuroscience↗

bioRxiv2022

Antisense, but not sense, repeat expanded RNAs activate PKR/eIF2α-dependent integrated stress response in C9orf72 FTD/ALS

GGGGCC (G4C2) hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). The repeat is bidirectionally transcribed and confers gain of toxicity. However, the underlying toxic species is debated, and it is not clear whether antisense CCCCGG (C4G2) repeat expanded RNAs contribute to disease pathogenesis. Our study shows that C9orf72 (C4G2) antisense repeat expanded RNAs trigger the activation of the PKR/eIF2-dependent integrated stress response independent of dipeptide repeat proteins that are produced through repeat-associated non-AUG initiated translation, leading to global translation inhibition and stress granule formation. Increased phosphorylation of PKR/eIF2 is also observed in the frontal cortex of C9orf72 FTD/ALS patients. Finally, only antisense (C4G2), but not sense (G4C2), repeat expanded RNAs can activate the PKR/eIF2 pathway. These results provide a mechanism by which antisense repeat expanded RNAs elicit neuronal toxicity in FTD/ALS caused by C9orf72 repeat expansions.

neuroscience↗