Amyloid precursor-like protein 2 cleavage contributes to neuronal intranuclear inclusions and cytotoxicity in spinocerebellar ataxia-7 (SCA7).
In spinocerebellar ataxia-7 (SCA7), a polyglutamine (polyQ) expansion in the ataxin-7 protein leads to the formation of neuronal intranuclear inclusions (NIIs) and neurodegeneration. In this study, amyloid precursor-like protein 2 (APLP2) was identified as a partner protein for ataxin-7. APLP2, belonging to the APP gene family, undergoes secretase and caspase cleavages and has been implicated in the pathogenesis of Alzheimer's disease (AD). Activated caspase-3 cleaves APP family proteins to release N-terminal fragments (NTFs) and intracellular C-terminal domains (ICDs), which can translocate into the nucleus and induce neurotoxicity in AD. Here, we report abnormal nuclear relocation of APLP2 and detection of NTFs in NIIs in SCA7. The ICDs generated by caspase-3 cleavage of APLP2 accumulate in nuclei and contribute to a cumulative toxicity when coexpressed with mutated ataxin-7. Our data suggest that the interaction between APLP2 and ataxin-7 and proteolytic processing of APLP2 may contribute to the pathogenesis of SCA7.
Takahashi-Fujigasaki
Junko
J
Jikei University School of Medicine, Division of Neuropathology, 3-25-8 Nishi-Shinbashi, Minato-ku, 105-8461, Tokyo, Japan.
Breidert
Tilo
T
Fujigasaki
Hiroto
H
Duyckaerts
Charles
C
Camonis
Jacques H
JH
Brice
Alexis
A
Lebre
Anne-Sophie
AS
D000328:Adult; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000067719:Ataxin-7; D002648:Child; D006801:Humans; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity; D011499:Protein Processing, Post-Translational / Q000235:genetics; D051381:Rats; D020754:Spinocerebellar Ataxias / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
C084104:APLP2 protein, human; C000593829:ATXN7 protein, human; D016564:Amyloid beta-Protein Precursor; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; C000593832:Atxn7 protein, rat; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments