A conserved MTMR lipid phosphatase increasingly suppresses autophagy in brain neurons during aging

Abstract

Ageing is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials in many cells at advanced ages. Here we show that age-associated defects in autophagic degradation occur at both the early and late stages of the process. Furthermore, in the fruit fly Drosophila melanogaster, the myotubularin-related (MTMR) lipid phosphatase egg-derived tyrosine phosphatase (EDTP) known as an autophagy repressor gradually accumulates in brain neurons during the adult lifespan. The age-related increase in EDTP activity is associated with a growing DNA N6-adenine methylation at EDTP locus. MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. Thus, EDTP, and presumably MTMR14, promotes brain ageing by increasingly suppressing autophagy throughout adulthood. We propose that EDTP and MTMR14 phosphatases operate as endogenous pro-ageing factors setting the rate at which neurons age largely independently of environmental factors, and that autophagy is influenced by DNA N6-methyladenine levels in insects.

The Small-Molecule Enhancers of Autophagy AUTEN-67 and -99 Delay Ageing in Drosophila Striated Muscle Cells

“…These results indicate that autophagic activity gradually lowers with age in the examined tissue. Similar data have been previously obtained from other Drosophila tissues, including the nervous system [30,43]. Next, Ref(2)P levels were compared in the IFM between control and AUTEN-67/99-treated animals.…”

“…For example, muscle regeneration characterizing mammalian organisms, as well as the age-related loss of muscle mass, cannot be examined in the fruit fly [59][60][61][62]. As in the nervous system, the IFM has been shown to increase EDTP expression with age [30,31,63]. If the age-dependent increase in EDTP expression causes harmful protein dephosphorylation in muscle, it may be important to investigate the effect of AUTENs on phosphatase activity in IFM ageing in a future study.…”

“…Mammalian MTMR14/Jumpy (myotubularin-related/Jumpy lipid phosphatase) and its Drosophila orthologue EDTP (egg-derived tyrosine phosphatase) antagonize with the Vps34 complex in controlling autophagic degradation [29][30][31]. Indeed, defects in MTMR14/ Jumpy and EDTP functions lead to an enhanced activity of autophagy [29,32,33].…”

Potent New Targets for Autophagy Enhancement to Delay Neuronal Ageing

“…The following Drosophila stocks were used for gene silencing: 40D-UAS (as an RNAi control—VDRC:60101), w 1118 ; P{GD11800}v40337 (UAS-Rab7-RNAi—VDRC: 40337), w * , Arl8[NIG.7891R (UAS-Arl8-RNAi—VDRC: 7891R-2), P{KK107630}VIE-260B (UAS-Rab2-RNAi—VDRC: v105358). We also used y 1 w * ; P{w[+mC] = UAST-YFP.Rab2}l(3)neo38 02 /TM3, Sb 1 (UAS-Rab2-WT—BDSC:23246) flies to compare the overexpression of wild-type Rab2 to the overexpression of a constitutively active form of Rab2 (Rab2 CA), and y * w * ; P{UAS-Luc.VALIUM20}attP40 (UAS-Luc—gift of Tamás Lukácsovich [ 52 ]) to compensate 2 Gal4 sequences in a PD model w * ; P{UAS-Hsap\SNCA.A53T} [ 15 ]. (UAS-A53T—BDSC:8148).…”

“…Our previous study demonstrated that autophagic capacity gradually decreased in the brains of flies during ageing. In aged animals, decreased levels of early markers of autophagy, e.g., FYVE (Fab-1, YGL023, Vps27, and EEA1 domain)- and Atg5-labeled structures, indicate that fewer autophagosomes are formed, but the increased amount of Atg8a-positive structures and accumulation of lipid-conjugated Atg8a (Atg8a-II) show that autophagy is also impaired after autophagosome formation (when the structure fuses with a lysosome or the autolysosomal content is digested enzymatically) [ 52 ]. Thus, autophagy gradually declines with age in brain neurons due to the cumulative effect of suppressed autophagosome formation and compromised autolysosomal function.…”