What are the specific molecular mechanisms by which disease proteins disrupt Ca2+ homeostasis?

neurodegeneration open
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Description

The abstract states that amyloid beta-peptide, alpha-synuclein, and huntingtin adversely affect Ca2+ homeostasis by mechanisms that have been ‘elucidated recently’ but doesn’t specify these mechanisms. Understanding these pathways is critical for developing targeted therapeutics that could prevent Ca2±mediated neurodegeneration.

Gap type: unexplained_observation Source paper: Calcium and neurodegeneration. (None, None, PMID:17328689)

Resolution criteria

Resolved when an evidence artifact identifies the specific molecular mechanisms by which disease proteins (Aβ, α-synuclein, huntingtin) disrupt Ca2+ homeostasis, with one of: (1) systematic Ca2+ signaling screen using genetically encoded Ca2+ indicators (GECOs, GCamp6) in neurons expressing each disease protein, identifying the specific Ca2+ channel or pump disrupted (L-type VSCC, NMDA receptor, SERCA, mitochondrial Ca2+ uniporter) with >=30% change in Ca2+ transient amplitude or frequency, and rescue by channel-specific pharmacological or genetic modulation; (2) proteomic mapping of Ca2+ signaling protein complexes (IP-MS or BioID) in disease protein-expressing neurons, identifying >=5 shared or unique Ca2+ signaling proteins that interact with each disease protein, with >=2 validated in post-mortem brain tissue; (3) patient iPSC-derived neurons (AD, PD, HD) with Ca2+ imaging and patch-clamp electrophysiology, demonstrating that specific Ca2+ channel blockers (nifedipine, memantine, or dantrolene) rescue disease-specific Ca2+ phenotypes and improve neuronal viability with n >= 3 lines per disease.

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