Selective induction of Rab9-dependent alternative mitophagy using a synthetic derivative of isoquinoline alleviates mitochondrial dysfunction and cognitive deficits in Alzheimer's disease models

Article

Author: Nathan, Alen Benhur Pravin ; Um, Jee-Hyun ; Shin, Dong Jin ; Kim, Kyung Hwa ; Kim, Young Yeon ; Park, Hwan Tae ; Kim, Young Hye ; Jeong, Dae Jin ; Lee, Da Ye ; Nah, Jihoon ; Yun, Jeanho ; Yoo, Eunhee ; Jo, Jihoon ; Choi, Se Myeong ; Jeong, Jeong-Hee ; Kim, Dong Hyun ; Cho, Jong Hyun ; Shin, Hwa Kyoung

Rationale: Promotion of mitophagy is considered a promising strategy for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). The development of mitophagy-specific inducers with low toxicity and defined molecular mechanisms is essential for the clinical application of mitophagy-based therapy. The aim of this study was to investigate the potential of a novel small-molecule mitophagy inducer, ALT001, as a treatment for AD. Methods: ALT001 was developed through chemical optimization of an isoquinolium scaffold, which was identified from a chemical library screening using a mitophagy reporter system. In vitro and in vivo experiments were conducted to evaluate the potential of ALT001 as a mitophagy-targeting therapeutic agent and to investigate the molecular mechanisms underlying ALT001-induced mitophagy. The therapeutic effect of ALT001 was assessed in SH-SY5Y cells expressing mutant APP and mouse models of AD (5×FAD and PS2APP) by analyzing mitochondrial dysfunction and cognitive defects. Results: ALT001 specifically induces mitophagy both in vitro and in vivo but is nontoxic to mitochondria. Interestingly, we found that ALT001 induces mitophagy through the ULK1-Rab9-dependent alternative mitophagy pathway independent of canonical mitophagy pathway regulators such as ATG7 and PINK1. Importantly, ALT001 reverses mitochondrial dysfunction in SH-SY5Y cells expressing mutant APP in a mitophagy-dependent manner. ALT001 induces alternative mitophagy in mice and restores the decreased mitophagy level in a 5×FAD AD model mouse. In addition, ALT001 reverses mitochondrial dysfunction and cognitive defects in the PS2APP and 5×FAD AD mouse models. AAV-mediated silencing of Rab9 in the hippocampus further confirmed that ALT001 exerts its therapeutic effect through alternative mitophagy. Conclusion: Our results highlight the therapeutic potential of ALT001 for AD via alleviation of mitochondrial dysfunction and indicate the usefulness of the ULK1-Rab9 alternative mitophagy pathway as a therapeutic target.

01 Jul 2000·Infection and ImmunityQ2 · MEDICINE

The Abundant Larval Transcript-1 and -2 Genes ofBrugia malayiEncode Stage-Specific Candidate Vaccine Antigens for Filariasis

Q2 · MEDICINE

Article

Author: Allen, Judith E. ; Maizels, Rick M. ; Gregory, William F. ; Atmadja, Agnes K.

ABSTRACTLymphatic filariasis is a major tropical disease caused by the mosquito-borne nematodesBrugiaandWuchereria. About 120 million people are infected and at risk of lymphatic pathology such as acute lymphangitis and elephantiasis. Vaccines against filariasis must generate immunity to the infective mosquito-derived third-stage larva (L3) without accentuating immunopathogenic responses to lymphatic-dwelling adult parasites. We have identified two highly expressed genes, designated abundant larval transcript-1 and -2 (alt-1andalt-2), from each of which mRNAs account for >1% of L3 cDNAs. ALT-1 and ALT-2 share 79% amino acid identity across 125 residues, including a putative signal sequence and a prominent acidic tract. Expression ofalt-1andalt-2is initiated midway through development in the mosquito, peaking in the infective larva and declining sharply following entry into the host. Humans exposed toBrugia malayishow a high frequency of immunoglobulin G1 (IgG1) and IgG3 antibodies to ALT-1 and -2, distinguishing them from adult-stage antigens, which are targeted by the IgG4 isotype. Immunization of susceptible rodents (jirds) with ALT-1 elicited a 76% reduction in parasite survival, the highest reported for a single antigen from any filarial parasite. ALT-1 and the closely related ALT-2 are therefore strong candidates for a future vaccine against human filariasis.

Allergologia et immunopathologiaQ4 · MEDICINE

Allergy to Alternaria. II. Diagnostic comparison of skin-tests and RAST.

Q4 · MEDICINE

Article

Author: Tapias, G ; Randazzo, L ; Granel, C ; Olivé, A ; Valencia, M

The diagnosis of Alternaria allergy is difficult and tests in vivo and in vitro usually do not give results as satisfactory as those obtained with other allergens. We studied 33 patients with a cutaneous response of 2 mm2 or more to skin-prick tests for Alternaria (extract containing 104 micrograms/ml of Alt-1). Results were compared with those of RAST. Skin tests were positive in 75.8% of cases (the resulting papule was the same size as or larger than that elicited by 10 mg/ml histamine) and negative in 24.2% of cases. RAST was positive in 75% of cases and negative in 25%. There was no significant difference in the frequencies. RAST was positive four times more often in males than in females; when these figures were corrected for population data, the ratio was 2:1. The coefficient of correlation between the intensity of skin-test and RAST results was r = 0.51 (p < 0.05). These findings are evaluated and results are discussed.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Arterial Hypertension	Preclinical	Austria	Alterras Therapeutics GmbH	-

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