Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy

Tam T. Quach, Harrison J. Stratton, Rajesh Khanna, Sabrina Mackey-Alfonso, Nicolas Deems, Jérome Honnorat, Kathrin Meyer, Anne Marie Duchemin

Research output: Contribution to journalReview articlepeer-review

Abstract

Despite intense research into the multifaceted etiology of neurodegenerative diseases (ND), they remain incurable. Here we provide a brief overview of several major ND and explore novel therapeutic approaches. Although the cause (s) of ND are not fully understood, the accumulation of misfolded/aggregated proteins in the brain is a common pathological feature. This aggregation may initiate disruption of Ca++ signaling, which is an early pathological event leading to altered dendritic structure, neuronal dysfunction, and cell death. Presently, ND gene therapies remain unidimensional, elusive, and limited to modifying one pathological feature while ignoring others. Considering the complexity of signaling cascades in ND, we discuss emerging therapeutic concepts and suggest that deciphering the molecular mechanisms involved in dendritic pathology may broaden the phenotypic spectrum of ND treatment. An innovative multiplexed gene transfer strategy that employs silencing and/or over-expressing multiple effectors could preserve vulnerable neurons before they are lost. Such therapeutic approaches may extend brain health span and ameliorate burdensome chronic disease states.

Original languageEnglish (US)
Article number14188
JournalInternational journal of molecular sciences
Volume23
Issue number22
DOIs
StatePublished - Nov 2022

Keywords

  • calcium signaling
  • CRMP3/DPYSL4
  • dendritic dystrophy
  • dysproteostasis
  • gene therapy
  • neurodegeneration
  • neuronal vulnerability

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Fingerprint

Dive into the research topics of 'Neurodegenerative Diseases: From Dysproteostasis, Altered Calcium Signalosome to Selective Neuronal Vulnerability to AAV-Mediated Gene Therapy'. Together they form a unique fingerprint.

Cite this