Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.
Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.
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DOI：
10.1186/s13024-023-00621-8
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发表时间：
2023-05-02
影响因子：
15.1
通讯作者：
Kao, Aimee W.
中科院分区：
文献类型：
--
作者：
Sampognaro, Paul J.;Arya, Shruti;Knudsen, Giselle M.;Gunderson, Emma L.;Sandoval-Perez, Angelica;Hodul, Molly;Bowles, Katherine;Craik, Charles S.;Jacobson, Matthew P.;Kao, Aimee W.
α-突触核蛋白、TDP-43和tau的常染色体显性突变被认为通过增强蛋白质聚集而易患神经变性。虽然α-突触核蛋白、TDP-43和tau突变的子集已显示增加这些蛋白质朝向自缔合的结构倾向，但聚集速率也高度依赖于蛋白质稳态浓度，这在很大程度上受其溶酶体降解速率调节。先前的研究已经表明，溶酶体蛋白酶精确地而不是不加选择地操作，在非常特定的线性氨基酸序列处切割其底物。根据这些知识，我们假设α-突触核蛋白、TDP-43和tau中的某些编码突变可能导致蛋白稳态浓度增加，并通过另一种机制最终聚集，即通过破坏溶酶体蛋白酶切割识别基序，随后赋予这些蛋白质蛋白酶抗性。为了测试这种可能性，我们首先生成了包含α-突触核蛋白、TDP-43和tau的所有潜在溶酶体蛋白酶切割位点的综合蛋白水解图谱。这些图谱的计算机分析表明，某些突变会减少组织蛋白酶切割，我们利用体外蛋白酶测定证实了这一预测。然后，我们在细胞模型和诱导的神经元中验证了这些发现，证明α-突触核蛋白，TDP-43和tau的突变形式的降解效率低于野生型，尽管它们以相似的速率进入溶酶体。总之，这项研究提供的证据表明，致病突变的N-末端结构域的α-突触核蛋白（G51D，A53T），TDP-43的低复杂度结构域（A315T、Q331K、M337V）和tau的R1和R2结构域（K257 T，N279 K，S305 N）直接损害其自身的溶酶体降解，通过延长这些蛋白质的降解半衰期来改变蛋白质体内平衡和增加细胞蛋白质浓度。这些结果还指出了新的、共有的、替代的机制，通过该机制，可能出现不同形式的神经变性，包括突触核蛋白病、TDP-43蛋白病和tau蛋白病。重要的是，它们还提供了如何将特定溶酶体蛋白酶的上调作为人类神经退行性疾病的潜在治疗剂的路线图。在线版本包含补充材料，可通过10.1186/s13024 - 023 - 00621 - 8获得。
Autosomal dominant mutations in α-synuclein, TDP-43 and tau are thought to predispose to neurodegeneration by enhancing protein aggregation. While a subset of α-synuclein, TDP-43 and tau mutations has been shown to increase the structural propensity of these proteins toward self-association, rates of aggregation are also highly dependent on protein steady state concentrations, which are in large part regulated by their rates of lysosomal degradation. Previous studies have shown that lysosomal proteases operate precisely and not indiscriminately, cleaving their substrates at very specific linear amino acid sequences. With this knowledge, we hypothesized that certain coding mutations in α-synuclein, TDP-43 and tau may lead to increased protein steady state concentrations and eventual aggregation by an alternative mechanism, that is, through disrupting lysosomal protease cleavage recognition motifs and subsequently conferring protease resistance to these proteins. To test this possibility, we first generated comprehensive proteolysis maps containing all of the potential lysosomal protease cleavage sites for α-synuclein, TDP-43 and tau. In silico analyses of these maps indicated that certain mutations would diminish cathepsin cleavage, a prediction we confirmed utilizing in vitro protease assays. We then validated these findings in cell models and induced neurons, demonstrating that mutant forms of α-synuclein, TDP-43 and tau are degraded less efficiently than wild type despite being imported into lysosomes at similar rates. Together, this study provides evidence that pathogenic mutations in the N-terminal domain of α-synuclein (G51D, A53T), low complexity domain of TDP-43 (A315T, Q331K, M337V) and R1 and R2 domains of tau (K257T, N279K, S305N) directly impair their own lysosomal degradation, altering protein homeostasis and increasing cellular protein concentrations by extending the degradation half-lives of these proteins. These results also point to novel, shared, alternative mechanism by which different forms of neurodegeneration, including synucleinopathies, TDP-43 proteinopathies and tauopathies, may arise. Importantly, they also provide a roadmap for how the upregulation of particular lysosomal proteases could be targeted as potential therapeutics for human neurodegenerative disease. The online version contains supplementary material available at 10.1186/s13024-023-00621-8.
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DOI：
10.1155/2015/546462
发表时间：
2015
期刊：
Parkinson's disease
影响因子：
--
作者：
Ferese R;Modugno N;Campopiano R;Santilli M;Zampatti S;Giardina E;Nardone A;Postorivo D;Fornai F;Novelli G;Romoli E;Ruggieri S;Gambardella S
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Gambardella S
影响因子：
16.8
作者：
Cao, Qin;Boyer, David R.;Eisenberg, David S.
通讯作者：
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影响因子：
4.5
作者：
Butler, Victoria J.;Gao, Fuying;Kao, Aimee W.
通讯作者：
Kao, Aimee W.
影响因子：
4.6
作者：
Alquezar, Carolina;Felix, Jessica B.;Kao, Aimee W.
通讯作者：
Kao, Aimee W.
影响因子：
82.9
作者：
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通讯作者：
Cuervo, Ana Maria