TAU x α-synuclein x APP x PRNP

Last update 23 Jan 2025

Basic Info

Related Targets

TAUα-synucleinAPP[+1]

Drugs associated with TAU x α-synuclein x APP x PRNP

NTP-288

Target

APP x PRNP x TAU x α-synuclein

Mechanism

APP inhibitors [+4]

Active Org.-

Originator Org.

Proclara Biosciences, Inc.

Active Indication-

Inactive Indication

Amyloidosis

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with TAU x α-synuclein x APP x PRNP

100 Translational Medicine associated with TAU x α-synuclein x APP x PRNP

0 Patents (Medical) associated with TAU x α-synuclein x APP x PRNP

Literatures (Medical) associated with TAU x α-synuclein x APP x PRNP

04 May 2022·AutophagyQ1 · BIOLOGY

Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models

Q1 · BIOLOGY

Article

Author: Winner, Beate ; Werner, Christian ; Marques, André R. A. ; Balta, Denise ; Prieto Huarcaya, Susy ; Gallwitz, Lisa ; Zunke, Friederike ; Xiang, Wei ; Sauer, Markus ; Stojkovska, Iva ; Rose-John, Stefan ; Fulzele, Amitkumar ; Belur, Nandkishore R. ; Fogh, Jens ; Rizo, Tania ; Di Spiezio, Alessandro ; Mazzulli, Joseph R ; Drobny, Alice ; Dejung, Mario ; Dobert, Jan Philipp ; Arnold, Philipp ; Saftig, Paul ; Bub, Simon

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates. We here postulate that SNCA degradation can be enhanced by the application of the recombinant human proform of CTSD (rHsCTSD). Our results reveal that rHsCTSD is efficiently endocytosed by neuronal cells, correctly targeted to lysosomes and matured to an enzymatically active protease. In dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the A53T mutation within the SNCA gene, we confirm the reduction of insoluble SNCA after treatment with rHsCTSD. Moreover, we demonstrate a decrease of pathological SNCA conformers in the brain and within primary neurons of a ctsd-deficient mouse model after dosing with rHsCTSD. Boosting lysosomal CTSD activity not only enhanced SNCA clearance in human and murine neurons as well as tissue, but also restored endo-lysosome and autophagy function. Our findings indicate that CTSD is critical for SNCA clearance and function. Thus, enzyme replacement strategies utilizing CTSD may also be of therapeutic interest for the treatment of PD and other synucleinopathies aiming to decrease the SNCA burden.Abbreviations: aa: amino acid; SNCA/α-synuclein: synuclein alpha; APP: amyloid beta precursor protein; BBB: blood brain barrier; BF: basal forebrain; CBB: Coomassie Brilliant Blue; CLN: neuronal ceroid lipofuscinosis; CNL10: neuronal ceroid lipofuscinosis type 10; Corr.: corrected; CTSD: cathepsin D; CTSB: cathepsin B; DA: dopaminergic; DA-iPSn: induced pluripotent stem cell-derived dopaminergic neurons; dox: doxycycline; ERT: enzyme replacement therapy; Fx: fornix, GBA/β-glucocerebrosidase: glucosylceramidase beta; h: hour; HC: hippocampus; HT: hypothalamus; i.c.: intracranially; IF: immunofluorescence; iPSC: induced pluripotent stem cell; KO: knockout; LAMP1: lysosomal associated membrane protein 1; LSDs: lysosomal storage disorders; MAPT: microtubule associated protein tau; M6P: mannose-6-phosphate; M6PR: mannose-6-phosphate receptor; MB: midbrain; mCTSD: mature form of CTSD; neurofil.: neurofilament; PD: Parkinson disease; proCTSD: proform of CTSD; PRNP: prion protein; RFU: relative fluorescence units; rHsCTSD: recombinant human proCTSD; SAPC: Saposin C; SIM: structured illumination microscopy; T-insol: Triton-insoluble; T-sol: Triton-soluble; TEM: transmission electron microscopy, TH: tyrosine hydroxylase; Thal: thalamus.

01 Jan 2018·Methods in Molecular Biology

Analysis of Covalent Modifications of Amyloidogenic Proteins Using Two-Dimensional Electrophoresis: Prion Protein and Its Sialylation

Article

Author: Baskakov, Ilia V ; Katorcha, Elizaveta

A number of proteins associated with neurodegenerative disease undergo several types of posttranslational modifications. They include N-linked glycosylation of the prion protein and amyloid precursor protein, phosphorylation of tau and α-synuclein. Posttranslational modifications alter physical properties of proteins including their net and surface charges, affecting their processing, life-time and propensity to acquire misfolded, disease-associated states. As such, analysis of posttranslational modifications is important for understanding the mechanisms of pathogenesis. Recent studies documented that sialylation of the disease-associated form of the prion protein or PrP^Sc controls the fate of prions in an organism and outcomes of prion infection. For assessing sialylation status of PrP^Sc, we developed a reliable protocol that involves two-dimensional electrophoresis followed by Western blot (2D). The current chapter describes the procedure for the analysis of sialylation status of PrP^Sc from various sources including central nervous system, secondary lymphoid organs, cultured cells, or PrP^Sc produced in Protein Misfolding Cyclic Amplification.

01 Jan 2013·Neurodegenerative DiseasesQ4 · MEDICINE

Neuropathology of Partial PGC-1α Deficiency Recapitulates Features of Mitochondrial Encephalopathies but Not of Neurodegenerative Diseases

Q4 · MEDICINE

Article

Author: Patrick Weydt ; Peter Klivenyi ; Albert C. Ludolph ; Imola Plangar ; Laszlo Vecsei ; Gabor G. Kovacs ; Levente Szalardy ; Denes Zadori

Background: Deficient peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) function is one component of mitochondrial dysfunction in neurodegenerative diseases. Current molecular classification of such diseases is based on the predominant protein accumulating as intra- or extracellular aggregates. Experimental evidence suggests that mitochondrial dysfunction and impaired protein processing are closely interrelated. In vitro findings further indicate that PGC-1α dysfunction may contribute to protein misfolding in neurodegeneration. Objective: To systematically evaluate the neuropathological alterations of mice lacking the expression of the full-length PGC-1α protein (FL-PGC-1α) but expressing an N-truncated fragment. Methods: To assess the pattern of neurodegeneration-related proteins, we performed immunostaining for Tau, pTau, α-synuclein, amyloid-β, amyloid precursor protein, prion protein, FUS, TDP-43 and ubiquitin. Using hematoxylin and eosin, Klüver-Barrera and Bielschowsky silver stainings and anti-GFAP immunohistochemistry, we performed an anatomical mapping to provide a lesion profile. Results: The immunohistochemical pattern of neurodegeneration-related proteins did not differ between FL-PGC-1α knockout and wild-type animals, and there was a complete lack of protein deposits or ubiquitin-positive inclusions. The analysis of neuropathological alterations revealed widespread vacuolation predominating in the cerebral white matter, caudate-putamen, thalamus and brainstem, and reactive astrogliosis in the brainstem and cerebellar nuclei. This morphological phenotype was thus reminiscent of human mitochondrial encephalopathies, especially the Kearns-Sayre syndrome. Conclusion: We conclude that the lack of FL-PGC-1α per se is insufficient to recapitulate major features of neurodegenerative diseases, but evokes a pathology seen in mitochondrial encephalopathies, which makes PGC-1α-deficient mice a valuable model for this yet incurable group of diseases.

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