Anti-apoptotic Splicing Variant of AIMP2 Recover Mutant SOD1-Induced Neuronal Cell Death

Kook, Myung Geun; Byun, Mi Ran; Lee, Soo Min; Lee, Min Hak; Lee, Dae Hoon; Lee, Hyung Been; Lee, Eui Jin; Baek, Kyunghwa; Kim, Sung Hoon; Kang, Kyung‐Sun; Choi, Jin Woo

doi:10.1007/s12035-022-03073-1

Cited by 2 publications

(2 citation statements)

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“…To elucidate which cell death pathway is most affected by the anti-apoptotic function of DX2, we treated various apoptotic stress on the neuroblastoma cell line SH-SY5Y. As described in previous papers [ 24 , 25 ], while AIMP2 induced cell death commonly under treated condition with most cell death inducing agents, DX2 effectively suppressed apoptosis (Fig. 1 A).…”

Section: Resultsmentioning

confidence: 69%

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Brain-targeted delivery of neuroprotective survival gene minimizing hematopoietic cell contamination: implications for Parkinson’s disease treatment

Lee,

Kang,

et al. 2024

J Transl Med

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Background Neurodegenerative diseases, including Parkinson's disease, Amyotropic Lateral Sclerosis (ALS) and Alzheimer's disease, present significant challenges for therapeutic development due to drug delivery restrictions and toxicity concerns. Prevailing strategies often employ adeno-associated viral (AAV) vectors to deliver neuroprotective survival genes directly into the central nervous system (CNS). However, these methods have been limited by triggering immunogenic responses and risk of tumorigenicity, resulting from overexpression of survival genes in peripheral blood mononuclear cells (PBMC), thereby increasing the risk of tumorigenicity in specific immune cells. Thus, by coding selectively suppressive microRNA (miRNA) target sequences in AAV genome, we designed CNS-targeted neuroprotective gene expression vector system without leakage to blood cells. Methods To minimize the potential for transgene contamination in the blood, we designed a CNS-specific AAV system. Our system utilized a self-complementary AAV (scAAV), encoding a quadruple repeated target sequence of the hematopoietic cell-specific miR142-3p at the 3' untranslated region (UTR). As a representative therapeutic survival gene for Parkinson’s disease treatment, we integrated DX2, an antagonistic splice variant of the apoptotic gene AIMP2, known to be implicated in Parkinson's disease, into the vector. Results This configuration ensured that transgene expression was stringently localized to the CNS, even if the vector found its way into the blood cells. A single injection of scAAV-DX2 demonstrated marked improvement in behavior and motor activity in animal models of Parkinson’s disease induced by either Rotenone or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Importantly, comprehensive preclinical data adhering to Good Laboratory Practice (GLP) standards revealed no adverse effects in the treated animals. Conclusions Our CNS-specific vector system, which encodes a survival transgene DX2, signifies a promising avenue for safe gene therapy, avoiding unintended expression of survival gene in blood cells, applicable to various neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 69%

“…Studies have shown that DX2 inhibits the cell death inducing activity of AIMP2, consequently promoting cell survival. The capability of DX2 to favor survival over death, particularly in the context of AIMP2 accumulation, offers profound implications for our understanding of PD and its potential treatment [ 24 , 25 ].…”

Section: Backgroundsmentioning

confidence: 99%