チャペロン媒介によるオートファギーは,神経転移性タンパク質の崩壊を防止する

Mathieu Bourdenx¹, Adrián Martín-Segura¹, Aurora Scrivo¹

¹Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Institute for Aging Studies of the Department of Medicine of the Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Cell

|April 23, 2021

まとめ

チャペロン媒介の自動死は,神経細胞のプロテオスタシスに不可欠であり,老化に関連したタンパク質の損傷と神経変異を予防します. CMAの強化はアルツハイマー病を軽減する

科学分野:

神経科学
分子生物学
細胞生物学

背景:

プロテオスタシス・ネットワークの衰えは老化と神経変異に寄与する.
ニューロンのタンパク質品質の制御が低下すると神経退行性疾患が起こります
チャペロン媒介の自動死 (CMA) は,神経変性に関係するタンパク質を分解する.

研究の目的:

ニューロンのプロテオスタシスにおけるCMAの役割を調査する.
CMAが神経機能とタンパク質の結合に及ぼす影響を理解する.
アルツハイマー病のような神経退行性疾患の治療対象として CMAを研究する

主な方法:

系統的および神経特異的なCMA阻害を有するマウスモデルを使用した.
神経機能,タンパク質変化,タンパク質毒性を分析した.
アルツハイマー病 (AD) のマウスモデルにおけるCMAの効果を評価した.
ADモデルのCMAの化学強化を使用した.

主要な成果:

ニューロンのCMAの喪失は脳の老化を模倣しニューロンの機能と転移性プロテオームを変化させます
CMA欠乏症はADの病態を悪化させ,結合傾向のあるタンパク質に悪影響を及ぼします.
CMAの化学増強はADの実験用マウスモデルで病理を改善した.

結論:

機能的なCMAはニューロンのプロテオスタシスの維持に不可欠です.
CMAは,誤った折り畳みのリスクの高いプロテオムのサブセットを保護します.
CMAをターゲットにすることで神経退行性疾患の治療戦略が生まれます

キーワード:

アルツハイマー病年老化付随する人オートファギーの化学活性化剤リソソーム神経変性タンパク質の集積タンパク質毒性過剰飽和したタンパク質タウ

さらに関連する動画

06:55

Using Caenorhabditis elegans to Screen for Tissue-Specific Chaperone Interactions

Published on: June 7, 2020

3.1K

08:59

4D Imaging of Protein Aggregation in Live Cells

Published on: April 5, 2013

17.6K

関連する概念動画

01:27

Autophagy

5.2K

Autophagy is a self-digesting process by which a cell protects itself from threats both within and outside the cell, ranging from abnormal proteins to invading bacteria. In this process, obsolete components of the cell and invading microbes are degraded by hydrolytic enzymes active in an acidic environment of the lysosomal lumen.
An autophagic pathway consists of a series of signaling events activated in response to diverse stress and physiological conditions such as food deprivation,...

5.2K

03:00

Molecular Chaperones and Protein Folding

18.9K

The native conformation of a protein is formed by interactions between the side chains of its constituent amino acids. When the amino acids cannot form these interactions, the protein cannot fold by itself and needs chaperones. Notably, chaperones do not relay any additional information required for the folding of polypeptides; the native conformation of a protein is determined solely by its amino acid sequence. Chaperones catalyze protein folding without being a part of the folded protein.
The...

18.9K

03:00

Molecular Chaperones and Protein Folding

14.1K

01:13

The Proteasome

1.3K

Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. This involves participation of a series of enzymes including— E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...

1.3K

02:18

The Proteasome

9.4K

Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
In this pathway, the target proteins are first tagged with small proteins called ubiquitin. A series of enzymes carry out the ubiquitination of the target proteins - E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3...

9.4K

01:26

Bacterial Protein Maturation

192

Bacterial protein maturation is a tightly regulated process that ensures newly synthesized polypeptides achieve correct functional conformations. This maturation involves a series of modifications, folding events, and quality control steps, often assisted by specialized chaperone proteins.N-Terminal ModificationsThe maturation of bacterial polypeptides begins cotranslationally as the polypeptide exits the ribosome. The first amino acid, N-formylmethionine (fMet), is typically modified at the...

192

関連する実験動画