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Chen ZC, Zhang W, Chua LL, Chai C, Li R, Lin L, Cao Z, Angeles DC, Stanton LW, Peng JH, Zhou ZD, Lim KL, Zeng L, Tan EK. Phosphorylation of amyloid precursor protein by mutant LRRK2 promotes AICD activity and neurotoxicity in Parkinson's disease. Sci Signal. 2017 Jul 18;10(488) PubMed.
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Chiesi Farmaceutici S.p.A.
Chen and colleagues have proposed a new pathophysiological role for AICD in PD pathogenesis. They showed that LRRK2 phosphorylated APP at Thr668, and that this further promoted the nucleus transcriptional activity of AICD, and its translocation to the nucleus to enhance LRRK2G2019S-induced neurotoxicity.
The AICD has been shown to be involved in a variety of signaling processes, many of which are potentially relevant to AD pathology (Ghosal et al., 2009). The best-known AICD interactor is the adaptor protein Fe65, which stabilizes the AICD and promotes its nuclear translocation (Beckett et al., 2012). In the nucleus, the AICD has been reported to be present within dot-like structures also containing Fe65 and the histone acetyl-transferase Tip60 (Kimberly et al., 2001).
This multiprotein complex is involved in transcriptional activation, though the specific role of the AICD in such a process, its full set of partner proteins, as well as the range of genes it can target are still debated (Hébert et al., 2006). The best-established AICD target gene codes for the pro-apoptotic tetraspannin KAI1, also known as CD82 (von Rotz et al., 2004). Thus, it would be interesting to know which specific genes are activated upon LRRK2-induced AICD stimulation and if they differ from those induced in AD cellular models.
References:
Ghosal K, Vogt DL, Liang M, Shen Y, Lamb BT, Pimplikar SW. Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18367-72. PubMed.
Beckett C, Nalivaeva NN, Belyaev ND, Turner AJ. Nuclear signalling by membrane protein intracellular domains: the AICD enigma. Cell Signal. 2012 Feb;24(2):402-9. PubMed.
Kimberly WT, Zheng JB, Guénette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. PubMed.
Hébert SS, Serneels L, Tolia A, Craessaerts K, Derks C, Filippov MA, Müller U, De Strooper B. Regulated intramembrane proteolysis of amyloid precursor protein and regulation of expression of putative target genes. EMBO Rep. 2006 Jul;7(7):739-45. PubMed.
von Rotz RC, Kohli BM, Bosset J, Meier M, Suzuki T, Nitsch RM, Konietzko U. The APP intracellular domain forms nuclear multiprotein complexes and regulates the transcription of its own precursor. J Cell Sci. 2004 Sep 1;117(Pt 19):4435-48. PubMed.
Indiana University School of Medicine
My overall feeling is that this paper is exciting in that it potentially shows a direct interaction between a protein associated with Parkinson's disease, LRRK2, and another protein involved in Alzheimer's disease, APP, thereby suggesting a potentially common pathway between the two neurodegenerative diseases.
This potential linkage between the two diseases is not surprising, because clues for such have been observed for more than 20 years. One of the first clues linking the pathology of Alzheimer's with that of Parkinson's disease was described in by Uéda et al. in 1993, when they sequenced a major protein found in amyloid plaque of Alzheimer's brain samples. They called this protein NACP (for non-amyloid component precursor, and now known as α-synuclein), which a few years later was recognized as the major component of Lewy bodies found in Parkinson's disease brains.
What makes the linkage of LRRK2 with Alzheimer's disease particularly exciting to me is that LRRK2 is an enzyme whose activity we might be able to modulate for therapeutic purposes, thus potentially providing a new avenue for the development of new treatments for Alzheimer's and other neurodegenerative diseases.
A broader implication is that studying other neurodegenerative diseases, including Parkinson's, ALS, and Huntington's disease, also leads to a better understanding of Alzheimer's disease.
References:
Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11282-6. PubMed.
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