Lamin Mutations Accelerate Aging via Defective Export of Mitochondrial mRNAs through Nuclear Envelope Budding

Abstract

SUMMARY Defective RNA metabolism and transport are implicated in aging and degeneration[1, 2], but the underlying mechanisms remain poorly understood. A prevalent feature of aging is mitochondrial deterioration[3]. Here we link a novel mechanism for RNA export through nuclear envelope (NE) budding[4, 5] that requires A-type Lamin, an inner nuclear membrane-associated protein, to accelerated aging observed in Drosophila LaminC (LamC) mutations. These LamC mutations were modeled after A-Lamin (LMNA) mutations causing progeroid syndromes (PS) in humans. We identified mitochondrial assembly regulatory factor (marf), a mitochondrial fusion factor (mitofusin), as well as other transcripts required for mitochondrial integrity and function, in a screen for RNAs that exit the nucleus through NE-budding. PS-modeled LamC mutations induced premature aging in adult flight muscles, including decreased levels of specific mitochondrial protein transcripts (RNA) and progressive mitochondrial degradation. PS-modeled LamC mutations also induced the accelerated appearance of other phenotypes associated with aging, including a progressive accumulation of poly-ubiquitin aggregates[6, 7] and myofibril disorganization[8, 9]. Consistent with these observations, the mutants had progressive jumping and flight defects. Downregulating marf alone induced the above aging defects. Nevertheless, restoring marf was insufficient for rescuing the aging phenotypes in PS-modeled LamC mutations, as other mitochondrial RNAs are affected by inhibition of NE-budding. Analysis of NE-budding in dominant and recessive PS-modeled LamC mutations suggests a mechanism by which abnormal lamina organization prevents the egress of these RNAs via NE-budding. These studies connect defects in RNA export through NE-budding to progressive loss of mitochondrial integrity and premature aging.

Nuclear Export Through Nuclear Envelope Remodeling inSaccharomyces cerevisiae

“…What are the cellular processes during which the pathway is used (e.g. during Drosophila NMJ development (Fradkin and Budnik, 2016;Speese et al, 2012), or proper mitochondrial function (Li et al, 2016)?…”

Differential Influence of Sample Sex and Neuronal Maturation on mRNA and Protein Transport in Induced Human Neurons

“…FISH was performed as described previously (Li et al, 2016) with modifications. Briefly, cultured neurons were washed once with DPBS (Gibco) and fixed with 4% PFA in PBS for 30 min at RT.…”

“…The distribution of total poly(A) RNAs in single diMNs was measured by FISH with oligo-dT probes as previously described (Packard et al, 2015;Li et al, 2016). Following hybridization, immunostaining of microtubule-associated protein 2 (MAP2) was used to identify the soma, and the DNA dye HST was used to define the nucleus.…”

Disease modeling with human neurons reveals LMNB1 dysregulation underlying DYT1 dystonia

“…In torsin mutants, disruption of mRNA nuclear export led to slowed growth and impaired development and plasticity of neuromuscular junctions 14 . To examine whether mRNA export was similarly impaired in DYT1 diMNs, we performed fluorescence in situ hybridization (FISH), as previously described 25,33,34 . We used digoxigenin-labeled oligo-dT as probes to detect the subcellular distribution of Poly (A) mRNAs.…”