An Evolutionarily Conserved Role of Presenilin in Neuronal Protection in the Aging Drosophila Brain

Abstract

Mutations in the genes are the major genetic cause of Alzheimer's disease. Presenilin and Nicastrin are essential components of γ-secretase, a multi-subunit protease that cleaves Type I transmembrane proteins. Genetic studies in mice previously demonstrated that conditional inactivation of Presenilin or Nicastrin in excitatory neurons of the postnatal forebrain results in memory deficits, synaptic impairment, and age-dependent neurodegeneration. The roles of () and () in the adult fly brain, however, are unknown. To knockdown (KD) or selectively in neurons of the adult brain, we generated multiple shRNA lines. Using a ubiquitous driver, these shRNA lines resulted in 80-90% reduction of mRNA and pupal lethality-a phenotype that is shared with and mutants carrying nonsense mutations. Furthermore, expression of these shRNAs in the wing disc caused notching wing phenotypes, which are also shared with and mutants. Similar to , neuron-specific KD using two independent shRNA lines led to early mortality and rough eye phenotypes, which were rescued by a fly transgene. Interestingly, conditional KD (cKD) of or in adult neurons using the and system caused shortened lifespan, climbing defects, increases in apoptosis, and age-dependent neurodegeneration. Together, these findings demonstrate that, similar to their mammalian counterparts, Psn and Nct are required for neuronal survival during aging and normal lifespan, highlighting an evolutionarily conserved role of Presenilin in neuronal protection in the aging brain.

Dominant negative mechanism of Presenilin-1 mutations in FAD

“…The presenilin hypothesis, which posits that PSEN mutations cause FAD via a loss of essential presenilin functions in the brain, was prompted by the age-dependent cortical neurodegeneration and dementia observed in Psen conditional double-knockout mice (3)(4)(5), along with the lack of neurodegeneration reported in transgenic mice overexpressing PSEN1 mutations (6, 7). The hypothesis was further supported subsequently by genetic findings in the Drosophila and mouse brain showing that partial loss of PS function also results in age-dependent neurodegeneration (8,9), and by studies in cultured cells and knock-in mouse brains demonstrating that PSEN1 mutations cause loss of γ-secretase activity and impair essential PS functions in learning and memory, synaptic function, and neuronal survival (10)(11)(12)(13). The findings from these mammalian studies are consistent with genetic data obtained in Caenorhabditis elegans and Drosophila showing that relative to wildtype PS1, mutant PS1 exhibited reduced biological activities (14,15).…”

Unraveling Novel Mechanisms of Neurodegeneration Through a Large-Scale Forward Genetic Screen in Drosophila

“…However, neuronal knockdown of Presenilin or other γ-secretase complex subunits such as Nicastrin revealed that γ-secretase activity is essential for neuronal maintenance. These flies exhibited shortened life-span and age-dependent climbing defects accompanied by histological signs of neurodegeneration (Kang et al, 2017). Interestingly, brain specific knockout of Psen1 , Psen2 or Nicastrin in mice also results in neurodegenerative features independent of β-amyloid accumulation (Beglopoulos et al, 2004; Feng et al, 2004; Saura et al, 2004; Tabuchi et al, 2009), pointing to an evolutionarily conserved function of the γ-secretase complex in neuronal maintenance.…”

Cell-autonomous role of Presenilin in age-dependent survival of cortical interneurons

“…Previous genetic studies demonstrated that selective inactivation of PS in excitatory neurons of the cerebral cortex results in age-dependent, progressive neurodegeneration including increases of apoptosis and gliosis [ 11 – 13 , 16 ]. Subsequent studies further showed that partial reduction of PS expression in excitatory neurons of the mouse cerebral cortex or in neurons of the Drosophila brain also causes age-dependent neurodegeneration and increases of apoptosis [ 17 , 43 ]. In this study, we continue this reductionist approach to dissect the role of PS in inhibitory interneurons of the cerebral cortex through the generation and analysis of IN- PS cDKO mice, in which PS expression is selectively inactivated in inhibitory interneurons using GAD2-IRES-Cre , which was shown previously to drive Cre-mediated recombination in > 90% cortical interneurons [ 34 ].…”

“…Surprisingly, no neuronal loss was observed in the cerebral cortex of Notch1/2 cDKO mice [ 58 ] and APP/APLP1/APLP2 conditional triple knockout mice [ 59 ], demonstrating that PS mediated cortical neuronal survival is not regulated through the Notch or APP family. Given the fact at any given time only 0.1–0.2% of excitatory or inhibitory cortical neurons lacking PS undergo apoptosis, making it impossible to perform biochemical analysis to gain insight into the molecular mechanism, we have therefore developed Drosophila models [ 43 ] and are now looking for genes that modulate age-dependent neurodegeneration caused by partial loss of Psn, the Drosophila homolog of Presenilin .…”