Abstract
Neuronal aging involves a progressive decline in cognitive abilities and loss of motor function. Mutations in human Lamin genes (LMNA, LMNB1, LMNB2) lead to a wide-range of diseases including muscular dystrophy, peripheral neuropathy and progeria. Here we investigate the role of neuronal Lamin in regulating age-related phenotypes. Neuronal targeting of Lamin led to shortened lifespan, progressive impairment of motor function and loss of dopaminergic (DA) neurons within the protocerebral anterior medial (PAM) cluster in the Drosophila melanogaster brain. Loss of neuronal Lamin caused an age-related decline in neural physiology, with slower neurotransmission and increased chance of motor circuit failure with age. Unexpectedly, Lamin-dependent decline in motor function was specific for the chemical synapses of the dorsal longitudinal muscle (DLM). Together these findings highlight a central role for Lamin dysfunction in regulating neuronal survival and motor circuit physiology during aging.
Highlights
Nuclear architecture and nuclear membrane function is a critical regulator of the aging process [1]
In Drosophila, it has been shown that neurons within the protocerebral anterior medial (PAM) cluster on the anterior side of the fly brain are responsible for startle-induced locomotor function (Fig 2D) [17]
Neuronal Lamin knockdown animals displayed no apparent loss of DA neurons across most areas of the brain (Fig 2A-C, G, S2A-D, I), we did observe a progressive loss of DA neurons within the PAM cluster (Fig 2D-F, S2E-H), and this effect was most pronounced in aged animals (Fig 2H)
Summary
Nuclear architecture and nuclear membrane function is a critical regulator of the aging process [1]. The nuclear lamina is a filamentous network that lines the inner nuclear membrane, providing a structural scaffold for the nucleus. This network is made up of type V intermediate filaments known as lamins that tether protein and chromatin complexes to the inner nuclear membrane. Mammals possess three lamin genes, an A-type gene, LMNA which encodes the alternatively spliced variants lamin A and lamin C, as well as two B-type genes, LMNB1 and LMNB2 [2]. Mutations in human Lamin genes (LMNA, LMNB1, LMNB2) cause a range of severe disorders termed laminopathies, which include muscular dystrophies, peripheral neuropathies and progeria, an accelerated aging syndrome [2]. Alterations in the nuclear lamina have been implicated in normal aging, suggesting that nuclear integrity and genomic stability are critical for cellular health throughout life [3]
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