Symposia
Interneuronal transmission of cytoplasmic disease proteins; the molecular mechanism and pathology／神経変性疾患病因タンパク質の神経細胞間伝播仮説の分子機構と病理 |
|---|
| 1S1-1
Prion-like properties of pathological protein aggregates in neurodegenerative diseases
Takashi Nonaka，Masato Hasegawa
Dementia Research Project, Tokyo Metropolitan Institute of Medical Science
Aberrant intracellular protein aggregates in affected neurons are neuropathological hallmarks of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), but it is unknown about the molecular mechanisms under which how these intracellular aggregates are formed in cells. Recent studies support that prion-like propagation of protein aggregates composed of tau, alpha-synuclein or TDP-43 may be involved in progression of AD, PD and ALS, respectively. This is related with findings that these pathologies spread in a stereotypical temporal and topological manner in human diseased brain. We have shown that alpha-synuclein and TDP-43 aggregates have prion-like properties, function as seeds for intracellular aggregation of monomeric proteins and propagate between cells using cell culture and animal models. These results suggest that prion-like propagation of abnormal protein aggregates may be involved in the pathogenesis of most neurodegenerative diseases. Our unique seeding models reproduce characteristic pathologies found in affected neurons of diseased brains, and are expected to be useful for screening of drug candidates for treatment or prevention of these diseases. | | 1S1-2
Emerging roles of exosomes in TDP-43 proteinopathy
Yohei Iguchi
Department of Neurology, Nagoya University Graduate School of Medicine
Aberrant cytoplasmic aggregation of TDP-43 in neurons and glial cells are a pathological hallmark of TDP-43 proteinopathy such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP). An initial symptom of ALS commonly appears at a single focal lesion, and it horizontally or vertically spreads, as if a “pathogen” contiguously or trans-synaptically transmits from cell to cell. The paradigm of prion-like propagation in TDP-43 proteinopathy has been speculated as the cause of the spreading as well as other neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease. There are some reports showing that insoluble fractions of ALS or FTLD-TDP brains acts as a seed of TDP-43 aggregation when it’s introduced in cultured cells, and that aggregation is transmitted to other cells. These data suggest that TDP-43 aggregation can be transmitted from cell to cell and it may explain the disease spreading of TDP-43 proteinopathy. In addition, many lines of evidence suggest that exosomes can contribute to propagation of pathological proteins in neurodegenerative diseases. Therefore, we investigated the role of exosomes in secretion and propagation of TDP-43 aggregation. I will show the role of exosomes in TDP-43 metabolism and the consequence of the modification of exosome secretion in cultured cells or transgenic mice expressing human TDP-43 mutant. On receiving these results, I would like to discuss whether exosomes can be a potential therapeutic target for TDP-43 proteinopathy. | | 1S1-3
Endosomal pathway: a key regulator for prion-like phenomenon in synucleinopathy
Takafumi Hasegawa
Division of Neurology, Department of Neuroscience & Sensory Organs, Tohoku University Graduate School of Medicine
The presence of misfolded α-synuclein (aSyn)-positive intracellular inclusions in Parkinson’s disease (PD) and its related disorders provides a conceptual link that has led to the use of synucleinopathy as an umbrella term for these diseases. It has long been considered that aSyn solely exerts its physiological and pathogenic effects intracellularly. However, increasing evidence suggests that aSyn secreted into the extracellular environment can transfer from cell-to-cell, thereby affecting the physiological state of the neighboring cells in a prion-like manner. This scenario is also acceptable as a feasible explanation for the topographic spread of Lewy pathology proposed by Braak and his colleagues. In addition to PD, the intercellular transmission of aSyn can be assumed to be present in multiple system atrophy, in which widespread aSyn-positive inclusions are found in oligodendroglia, a type of cell that does not express aSyn under physiological condition. Endosomal pathway is a type of cellular logistics by which cargo molecules in transport vesicles are able to move between organelles and the plasma membrane. Hence, it is not surprising that endosomal pathway plays crucial roles in uptake, secretion and degradation of transmissible “prionoid” proteins. Given the potential role of extracellular aSyn as the culprit of disease progression, it makes sense to adopt antibody-based therapy for the clearance of transmissible aSyn species. Likewise, it could be possible to prevent pathological spreading by blocking endocytic processes of aSyn. In this talk, I wish to discuss the importance of the endosomal pathway as a proof-of-concept for the transcellular spreading phenomenon in synucleinopathy and argue its potential value as a target for disease modifying therapy. | | 1S1-4
Extracellular release of neurodegenerative proteins is regulated by DnaJC5/Hsc70 complexes
Laura J Blair
Department of Molecular Medicine, USF Health Byrd Institute
The accumulation of protein aggregates is a pathological hallmark of neurodegenerative diseases. It is known that these aggregating proteins can be found in extracellular space and can spread from neuron to neuron in a prion-like manner. However, the mechanisms regulating the trans-synaptic propagation, including the neuronal release of these proteins, remain under investigation. We recently identified a cysteine string protein, DnaJC5, which works together with the molecular chaperone Hsc70 to regulate the release of tau and other aggregating proteins, including α-synuclein and TDP-43. In primary neuron cultures, overexpression of DnaJC5 increased the levels of extracellular tau, while tau release was reduced in primary neuron cultures isolated from mice lacking DnaJC5. Moreover, Hsc70 ATPase activity and DnaJ binding, as well as the SNARE protein SNAP-23, are also required for this release mechanism. Further characterization has revealed that DnaJC5 palmitoylation is important for this activity. Overall, our data suggest that DnaJC5 and Hsc70 regulate a non-canonical pathway for release of tau and other proteins involved in neurodegenerative disease. Additional studies are in progress to measure the toxicity and potential of pathological propagation of tau species released through this mechanism. | | 1S1-5
Tunneling Nanotubes (TNTs): Structure, Formation and Role in Neurodegenerative Diseases Spreading
Chiara Zurzolo
Pasteur Institute
Neurodegenerative diseases (NDs) like Prion disease, Alzheimer’s (AD), Parkinson’s (PD) and Huntington’s (HD) disease are part of a larger group of protein misfolding disorders characterized by the progressive accumulation and spreading of different protein aggregates. Like Prions, misfolded forms of ASYN, tau, Abeta and Htt proteins associated with AD, PD and HD can be transmitted experimentally in cellular and in animal models where act as ‘seeds’ to recruit the endogenous protein into aggregates. However, the mechanism of intercellular transfer is still debated. We have recently described a novel mechanism of PrPSc transmission through Tunneling Nanotubes (TNTs) (1). TNTs are actin-based protrusions connecting cells in culture and represents a novel mechanism of cell-to-cell communication. Furthermore mutant polyQ Htt aggregates appear to highjack TNTs (2) as well as fibrillar and oligomeric ASYN assemblies (3) and Tau fibrils (4). We propose that TNTs contribute to the progression of the pathology of NDs by spreading in the brain of misfolded protein assemblies. Thus, understanding the mechanism of TNT formation is important to uncover their physiological function. We demonstrate that despite their similarities, filopodia and TNTs form through distinct molecular mechanisms (5) indicating that they are different structures. Finally, analysis by correlative cryo-EM and tomography (Sartori, et al.) show differences in the actin organization and appearance of the two structures revealing their unique identities. (1) Gousset et al, NCB, 2009 (2) Costanzo et al, JCS, 2013(3) Abounit et al, EMBO J 2016(4) Abounit et al, Prion 2016(5) Delage et a,l Sci Rep 2016 | | | |
|
|
