39 research outputs found
Dysfunction of Protein Quality control in Parkinsonism-Dementia complex of Guam
Guam parkinsonism-dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders.ArticleFRONTIERS IN NEUROLOGY.9:173(2018)journal articl
Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways
Amyotrophic lateral sclerosis (ALS) is a devastating
neurological disease with no effective treatment
available. An increasing number of genetic causes of ALS
are being identified, but how these genetic defects lead to
motor neuron degeneration and to which extent they affect
common cellular pathways remains incompletely understood.
To address these questions, we performed an interactomic
analysis to identify binding partners of wild-type
(WT) and ALS-associated mutant versions of ATXN2,
C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal
cells. This analysis identified several known but also many
novel binding partners of these proteins
Extraction of Dzyaloshinksii-Moriya interaction from propagating spin waves validated
The interfacial Dzyaloshinksii-Moriya interaction (iDMI) is of great interest
in thin-film magnetism because of its ability to stabilize chiral spin
textures. It can be quantified by investigating the frequency non-reciprocity
of oppositely propagating spin waves. However, as the iDMI is an interface
interaction the relative effect reduces when the films become thicker making
quantification more difficult. Here, we utilize all-electrical Propagating Spin
Wave Spectroscopy (PSWS) to disentangle multiple contributions to spin wave
frequency non-reciprocity to determine the iDMI. This is done by investigating
non-reciprocities across a wide range of magnetic layer thicknesses (from 4 to
26 nm) in Pt/Co/Ir, Pt/Co/Pt, and Ir/Co/Pt stacks. We find the expected sign
change in the iDMI when inverting the stack order, and a negligible iDMI for
the symmetric Pt/Co/Pt. We additionally extract a difference in surface
anisotropies and find a large contribution due to the formation of different
crystalline phases of the Co, which is corroborated using nuclear magnetic
resonance and high-resolution transmission-electron-microscopy measurements.
These insights will open up new avenues to investigate, quantify and
disentangle the fundamental mechanisms governing the iDMI, and pave a way
towards engineered large spin-wave non-reciprocities for magnonic applications.Comment: 12 pages, 2 figure
Endolysosomal pathway activity protects cells from neurotoxic TDP-43
The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP‑43). Using a yeast model for TDP‑43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP‑43. This clearance occurred via TDP‑43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP‑43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP‑43. In contrast, enhanced autophagy contributed to TDP‑43 cytotoxicity, despite being involved in TDP‑43 degradation. TDP‑43’s interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP‑43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP‑43-associated diseases
Comparative interactomics analysis of different ALS-associated proteins identifies converging molecular pathways
Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment available. An increasing number of genetic causes of ALS are being identified, but how these genetic defects lead to motor neuron degeneration and to which extent they affect common cellular pathways remains incompletely understood. To address these questions, we performed an interactomic analysis to identify binding partners of wild-type (WT) and ALS-associated mutant versions of ATXN2, C9orf72, FUS, OPTN, TDP-43 and UBQLN2 in neuronal cells. This analysis identified several known but also many novel binding partners of these proteins. Interactomes of WT and mutant ALS proteins were very similar except for OPTN and UBQLN2, in which mutations caused loss or gain of protein interactions. Several of the identified interactomes showed a high degree of overlap: shared binding partners of ATXN2, FUS and TDP-43 had roles in RNA metabolism; OPTN- and UBQLN2-interacting proteins were related to protein degradation and protein transport, and C9orf72 interactors function in mitochondria. To conf
Selective Transgenic Expression of Mutant Ubiquitin in Purkinje Cell Stripes in the Cerebellum
Dysfunction of Protein Quality Control in Parkinsonism–Dementia Complex of Guam
Guam parkinsonism–dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders