Alzheimer's disease‐causing proline substitutions lead to presenilin 1 aggregation and malfunction
作者： Tziona Ben‐Gedalya , Lorna Moll , Michal Bejerano‐Sagie , Samuel Frere , Wayne A Cabral
关键词: Genetics 、 Proteostasis 、 Cell culture 、 Biology 、 Knockout mouse 、 Alzheimer's disease 、 Chaperone (protein) 、 Protein folding 、 Endoplasmic reticulum 、 Presenilin
摘要: Abstract Do different neurodegenerative maladies emanate from the failure of a mutual protein folding mechanism? We have addressed this question by comparing mutational patterns that are linked to manifestation distinct disorders and identified similar neurodegeneration‐linked proline substitutions in prion presenilin 1 underlie development disorder familial Alzheimer9s disease (fAD), respectively. These were found prevent endoplasmic reticulum (ER)‐resident chaperone, cyclophilin B, assisting fold properly, leading its aggregation, deposition ER, reduction γ‐secretase activity, impaired mitochondrial distribution function. Similarly, reduced quantities processed, active observed brains B knockout mice. discoveries imply activity contributes disorders, propose novel mechanism for certain fAD cases, support emerging theme can stem aberrant This study also points at ER chaperones as targets counter‐neurodegeneration therapies.
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