Biology subjects

Pestronk, A.

Publications and source records attributed to Pestronk, A..

3 recordsLinked to original sources

bioRxiv2025

Expression of Fibroblast Growth Factor Receptor 3 (FGFR3) in the Human Peripheral Nervous System: Implications for the Putative Pathogenic Role of FGFR3 Autoantibodies in Neuropathy

IntroductionAutoantibodies to the Fibroblast Growth Factor Receptor 3 (FGFR3-AAbs) have been associated with idiopathic sensory-predominant neuropathy. The pathogenicity of FGFR3-AAbs in this disorder is unknown. Pathogenic mechanisms of autoantibodies in other dysimmune neuropathies commonly involve their direct binding to antigens on either neurons or glia. The expression of FGFR3 in the human peripheral nervous system is unknown. Therefore, as an initial step toward clarifying the pathogenicity of FGFR3-AAbs, we characterized the expression of FGFR3 in nerve (hNerve), dorsal root ganglia (hDRG) and spinal cord (hSC) in human. MethodsFGFR3 mRNA was assayed via in situ hybridization (ISH) on post-mortem sections of hNerve, hDRG and hSC, and by re-analysis of RNA-sequencing data from hDRG. FGFR3 protein was assayed in these tissues using capillary electrophoretic immunoassays (CEIA) with several validated anti-FGFR3 antibodies. ResultsFGFR3 mRNA was not detected in hNerve or hDRG but was abundant in hSC by ISH. FGFR3 protein was absent from hNerve and hDRG by CEIA but was moderately expressed in hSC. DiscussionA direct pathogenic mechanism of FGFR3-AAbs in sensory neuropathy would require the expression of FGFR3 in either neurons or non-neuronal cells in nerve or DRG. Using multiple methods, we did not detect FGFR3 expression at the mRNA or protein levels in these tissues. Given the absence of FGFR3 from hNerve and hDRG, it is improbable that FGFR3-AAbs cause direct damage to the neural components involved in neuropathy and thus are unlikely to be pathogenic, although indirect mechanisms via non-neural cells cannot be excluded.

neuroscience↗

bioRxiv2025

Identifying and treating CLN3 disease outside the central nervous system

Background and aimsSevere gastrointestinal (GI) symptoms occur in people with CLN3 disease, a neurodegenerative disorder. If left untreated these GI symptoms compromise life quality and may contribute to death. We hypothesized GI symptoms in CLN3 disease are at least partially due to neurodegeneration in the enteric nervous system (ENS), the master regulator of bowel function. MethodsWe examined the integrity of the ENS in human CLN3 autopsy small bowel and colon, and in CLN3 deficient (Cln3{Delta}ex7/8) mice. We performed detailed immunohistological analyses of enteric neurons and glia and assessed bowel transit times at multiple disease stages. We then tested the therapeutic potential of neonatal intravenous gene therapy (AAV9-hCLN3) to prevent bowel phenotypes in Cln3{Delta}ex7/8 mice. ResultsHuman CLN3 bowel displayed a profound loss of enteric neurons and their neurites, with pathological effects upon enteric glia. Cln3{Delta}ex7/8 mice had normal appearing ENS at 1 month of age, but then experienced progressive loss of both enteric neurons and glia accompanied by marked bowel distention, resembling the human CLN3 phenotype. Degenerative changes in Cln3{Delta}ex7/8 mouse enteric neurons and glia were largely prevented by systemic neonatal delivery of AAV9-hCLN3 gene therapy, preventing bowel distention at disease endstage. ConclusionsOur findings demonstrate that CLN3 deficiency profoundly damages enteric neurons and glia in both murine and human CLN3 disease, contributing to GI dysfunction. This study provides preclinical evidence that systemic gene therapy may effectively treat multiple aspects of bowel pathology, expanding the therapeutic landscape beyond the CNS. What you need to know: Background and ContextSignificant gastrointestinal (GI) symptoms are evident in many pediatric neurological conditions. We hypothesized that, in addition to central nervous system (CNS) effects, defects in the enteric nervous system (ENS) may underlie these GI symptoms in some neurodegenerative diseases. Revealing such defects would open up new opportunities for treating these life-limiting and debilitating symptoms. New FindingsThe enteric nervous system is significantly impacted in human CLN3 disease, a feature that is recapitulated in CLN3 mice. Progressive enteric neurodegeneration in these mice follows a similar time course to neuron loss in the brain, resulting in severe bowel distention. Nevertheless, bowel distention and the majority of the pathology within the enteric nervous system can be mitigated via neonatal gene therapy. LimitationsOur human data will need to be replicated in larger numbers of CLN3 cases, and methods will need to be developed to treat the human bowel, avoiding the risk of liver tumors. ImpactThese results reveal that a neurodegenerative disease previously thought to primarily affect the CNS, damages the bowels enteric nervous system and that ENS degeneration can be prevented in mice by gene therapy. These data provide a new perspective on this pediatric disorder and may have relevance to other pediatric neurologic diseases. Lay SummaryThe progressive loss of neurons in CLN3 disease is not confined to the brain but also occurs in the bowel enteric nervous system, contributing directly to GI dysfunction. Neurodegeneration in the enteric nervous system can be prevented by treating the bowel with gene therapy.

neuroscience↗

bioRxiv2024

Seeding competent TDP-43 persists in human patient and mouse muscle

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein that accumulates as aggregates in the central nervous system of some neurodegenerative diseases. However, TDP-43 aggregation is also a sensitive and specific pathologic feature found in a family of degenerative muscle diseases termed inclusion body myopathy (IBM). TDP-43 aggregates from ALS and FTD brain lysates may serve as self-templating aggregate seeds in vitro and in vivo, supporting a prion-like spread from cell to cell. Whether a similar process occurs in IBM patient muscle is not clear. We developed a mouse model of inducible, muscle-specific cytoplasmic localized TDP-43. These mice develop muscle weakness with robust accumulation of insoluble and phosphorylated sarcoplasmic TDP-43, leading to eosinophilic inclusions, altered proteostasis and changes in TDP-43-related RNA processing that resolve with the removal of doxycycline. Skeletal muscle lysates from these mice also have seeding competent TDP-43, as determined by a FRET-based biosensor, that persists for weeks upon resolution of TDP-43 aggregate pathology. Human muscle biopsies with TDP-43 pathology also contain TDP-43 aggregate seeds. Using lysates from muscle biopsies of patients with IBM, IMNM and ALS we found that TDP-43 seeding capacity was specific to IBM. Surprisingly, TDP-43 seeding capacity anti-correlated with TDP-43 aggregate and vacuole abundance. These data support that TDP-43 aggregate seeds are present in IBM skeletal muscle and represent a unique TDP-43 pathogenic species not previously appreciated in human muscle disease. SummaryTDP-43 aggregate seeds persist in mouse and human skeletal muscle independent of large TDP-43 inclusions.

pathology↗