14-3-3θ, a novel player in TDP-43 pathophysiology: Implications for ALS/FTD.

In this issue of Neuron, Ke et al. report a novel non-canonical interaction between 14-3-3θ and TDP-43 that impacts loss-of-function and gain-of-toxic pathology in TDP-43 proteinopathies. The authors further provide proof of principle for a 14-3-3θ-targeted gene therapy to reduce TDP-43-induced deficits in transgenic TDP-43 mutant mice.

Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies.

Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the precise mechanisms underlying the complexity of different types of tau pathology remain incompletely understood. Here we describe an approach for proteomic profiling of aggregate-associated proteomes on slides with formalin-fixed, paraffin-embedded (FFPE) tissue that utilizes proximity labelling upon high preservation of aggregate morphology, which permits the profiling of pathological aggregates regardless of their size.

Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery. Recent advances suggest that beyond their canonical role in the nuclear import of protein cargoes, nuclear-import receptors (NIRs) can prevent and reverse aberrant phase transitions of TDP-43, FUS, and related prion-like RBPs and restore their nuclear localization and function.

Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

Background: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-β1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology.

Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models.

In a subgroup of patients with amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD), the (G4C2)-RNA repeat expansion from C9orf72 chromosome binds to the Ran-activating protein (RanGAP) at the nuclear pore, resulting in nucleocytoplasmic transport deficit and accumulation of Ran in the cytosol. Here, we found that the sigma-1 receptor (Sig-1R), a molecular chaperone, reverses the pathological effects of (G4C2)-RNA repeats in cell lines and in Drosophila. The Sig-1R colocalizes with RanGAP and nuclear pore proteins (Nups) and stabilizes the latter.

Traffic jam at the nuclear pore: All roads lead to nucleocytoplasmic transport defects in ALS/FTD.

Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease.

Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis.

Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that not only regulates mitochondrial respiration but also controls cellular defense against ER and oxidative stress. This makes S1R a potential therapeutic target in amyotrophic lateral sclerosis (ALS). Especially, as a missense mutation E102Q in S1R has been reported in few familial ALS cases.

mRNP assembly, axonal transport, and local translation in neurodegenerative diseases.

The development, maturation, and maintenance of the mammalian nervous system rely on complex spatiotemporal patterns of gene expression. In neurons, this is achieved by the expression of differentially localized isoforms and specific sets of mRNA-binding proteins (mRBPs) that regulate RNA processing, mRNA trafficking, and local protein synthesis at remote sites within dendrites and axons. There is growing evidence that axons contain a specialized transcriptome and are endowed with the machinery that allows them to rapidly alter their local proteome via local translation and protein degradation.

Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency.

Mitochondrial defects associated with respiratory chain complex I deficiency lead to heterogeneous fatal syndromes. While the role of NDUFS8, an essential subunit of the core assembly of the complex I, is established in mitochondrial diseases, the mechanisms underlying neuropathology are poorly understood. We developed a Drosophila model of NDUFS8 deficiency by knocking down the expression of its fly homologue in neurons or in glial cells.

Mitochondrial quality control in amyotrophic lateral sclerosis: towards a common pathway?

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by loss of upper and lower motor neurons. Different mechanisms contribute to the disease initiation and progression, including mitochondrial dysfunction which has been proposed to be a central determinant in ALS pathogenesis. Indeed, while mitochondrial defects have been mainly described in ALS-linked SOD1 mutants, it is now well established that mitochondria become also dysfunctional in other ALS conditions.

Enhancing Mitofusin/Marf ameliorates neuromuscular dysfunction in Drosophila models of TDP-43 proteinopathies.

Transactive response DNA-binding protein 43 kDa (TDP-43) is considered a major pathological protein in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The precise mechanisms by which TDP-43 dysregulation leads to toxicity in neurons are not fully understood. Using TDP-43-expressing Drosophila, we examined whether mitochondrial dysfunction is a central determinant in TDP-43 pathogenesis.