First, mtDNA variations play an important role in neurodegenerative diseases, with deleterious mtDNA mutations causing early onset neurodegenerative disorders, and common mtDNA polymorphisms are associated with late-onset neurodegenerative disorders [1] [5].
One of the AβPP mutations causing early-onset familial AD, the Arctic mutation (AβPP E693G), has been shown to specifically increase the rate of formation of protofibrils [ 8, 45, 46].
As PS1 mutations causing early-onset AD modulate protein expression by disrupting endoplasmic reticulum homeostasis, to determine whether decreased Crif1 levels in Tg6799 and APP/PS1 mouse brains were caused by PS1 mutations, we measured Crif1 levels in the brains of 12-month-old Tg2576 mice that carry only the APP mutation (Supplementary Figure 1c).
If the CACNA1H M1549V mutation causes early-onset PA, CACNA1H (CaV3.2) should be expressed in human adrenal glomerulosa.
However, we also observed the spread of a mutation causing earlier aging of mothers whose negative effect was reset in the daughters.
However, mutations in FLCN associated with Birt Hogg Dubé syndrome are heterogeneous, and are often nonsense mutations or frameshift mutations that cause early truncation of the protein product at the carboxy-terminus.
These mutations were originally identified and characterised as fly and mouse embryonic lethal mutations that cause early cardiac failure (Schott et al., 1998).
Studies of mutations that cause early onset AD and promote Aβ accumulation in the brain strongly support the notion that inhibiting Aβ aggregation will prevent AD.
Among 20 HU and/or CPT-sensitive mutants, 12 mutants failed to express Swi3 as a 5FLAG fusion protein, suggesting that these mutants contain non-sense or frame-shift mutations that cause early termination of Swi3 translation (data not shown).
