Autophagy and neurodegeneration
The biology of diseases associated with protein misfolding and intracellular aggregation, using Huntington’s disease (HD) as a paradigm
Intracellular protein misfolding/aggregation are features of many late-onset neurodegenerative diseases, called proteinopathies. These include Alzheimer’s disease, Parkinson’s disease, tauopathies, and polyglutamine expansion diseases (like Huntington’s disease (HD) and various spinocerebellar ataxias (SCAs)). Currently, there are no effective strategies that slow/prevent the neurodegeneration resulting from these diseases in humans.
We are currently employing a range of approaches to address this issue, including conventional biochemistry and cell biology, zebrafish genetic knockdowns and genome-wide Drosophila modifier screens. We are trying to identify pathways that may have broad relevance to a range of neurodegenerative diseases (e.g. Sarkar et al. (2011) Mol Cell 43, 19-32).
Therapeutic strategies for these diseases
The mutations causing HD and many proteinopathies confer novel toxic functions on the specific protein, and disease severity frequently correlates with expression levels. Thus, it is important to understand the factors regulating the levels of these aggregate-prone proteins.
(Macro) autophagy is a bulk degradation process that mediates the clearance of long-lived proteins and organelles (reviewed in Rubinsztein et al. (2011) Cell 146, 682-695). Autophagosomes are formed by double-membraned structures, which engulf portions of cytoplasm. Autophagosomes ultimately fuse with lysosomes, where their contents are degraded.
We have become increasingly involved in studying autophagy, since the time of our discovery that it regulates the levels of intracytoplasmic aggregate-prone proteins that cause many neurodegenerative diseases, including Huntington’s disease, point mutations in alpha-synuclein (causing forms of Parkinson’s disease), and wild-type and mutant forms of tau (causing various dementias) (reviewed in Rubinsztein et al. (2012) Nature Reviews Drug Discovery 11:709-730). The clearance of such substrates is retarded in cell models when autophagy is compromised. For Huntington’s disease and a range of related neurodegenerative diseases, we are pursuing our findings that the toxicity of these proteins in cells, Drosophila, zebrafish and mice can be alleviated by enhancing their removal by autophagy (Ravikumar et al. (2004) Nature Genetics 36: 585-595). We are trying to identify safe and effective strategies for exploiting autophagy upregulation in order to enhance the removal of the toxic intracytoplasmic proteins that cause many of these diseases (e.g. Sarkar et al. (2007) Nature Chemical Biology 3: 331-338; Williams et al. (2008) Nature Chemical Biology 4: 295-305).
The cell biology of autophagy and its relevance to human physiology and disease, with a focus on the nervous system
We have identified the plasma membrane as a source of autophagosome membrane (Ravikumar et al. (2010) Nature Cell Biology 12:747-757) and have characterised early events in autophagosome biogenesis (e.g. Moreau et al. (2011) Cell 146:303-317; Puri et al. (2013) Cell 154: 1285-1299). We have studied how lysosomal positioning regulates autophagy (Korolchuk et al. (2011) Nature Cell Biology 13:453-460).
We have found that autophagy may be inhibited in various neurodegenerative diseases (e.g. Winslow et al. (2010) J Cell Biol 190:1023-1037) and have been trying to elucidate the pathological consequences of autophagy compromise — our data suggest that autophagy inhibition impairs flux through the ubiquitin-proteasome degradation pathway (Korolchuk et al. (2009) Molecular Cell 33:517-527).
M Jimenez-Sanchez, W Lam, M Hannus, B Sönnichsen, S Imarisio, A Fleming, A Tarditi, F Menzies, T Ed Dami, C Xu, E Gonzalez-Couto, G Lazzeroni, F Heitz, D Diamanti, L Massai, VP Satagopam, G Marconi, C Caramelli, A Nencini, M Andreini, GL Sardone6, NP Caradonna, V Porcari, C Scali, R Schneider, G Pollio, CJ O’Kane, A Caricasole and DC Rubinsztein. siRNA screen identifies QPCT as a druggable target for Huntington’s disease. Nature Chem. Biol. 11, 347-354 (2015).
M Vicinanza, VI Korolchuk, A Ashkenazi, C Puri, FM Menzies, JH Clarke and DC Rubinsztein. PI(5)P regulates autophagosome biogenesis. Mol. Cell 57, 219-234 (2015).
C Puri, M Renna, C Figueira Bento, K Moreau and DC Rubinsztein Diverse autophagosome membrane sources coalesce in recycling endosomes. Cell 154, 1285-1299 (2013).
S Luo, M Garcia-Arencibia, R Zhao, C Puri, PPC Toh, O Sadiq and DC Rubinsztein. Bim inhibits autophagy by recruiting Beclin 1 to microtubules. Mol. Cell 47, 359-370 (2012).
K Moreau, B Ravikumar, M Renna, C Puri, and DC Rubinsztein. Autophagosome precursor maturation requires homotypic fusion. Cell 146, 303-317 (2011).
S Sarkar, VI Korolchuk, M Renna, S Imarisio, A Fleming, A Williams, M Garcia-Arencibia, C Rose, S Luo, BR Underwood, G Kroemer, CJ O’Kane, and DC Rubinsztein Complex inhibitory effects of nitric oxide on autophagy. Mol. Cell 43, 19-32 (2011).
VI Korolchuk, S Saiki, M Lichtenberg, FH Siddiqi, EA Roberts, S Imarisio, L Jahreiss, S Sarkar, M Futter, FM Menzies, CJ O’Kane, V Deretic and DC Rubinsztein Lysosomal positioning coordinates cellular nutrient responses. Nature Cell Biol. 13, 453-460 (2011).
B Ravikumar, K Moreau, L Jahreiss, C Puri and DC Rubinsztein. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nature Cell Biol. 12:747-757 (2010).
AR Winslow, C-W Chen, S Corrochano, A Acevedo-Arozena, DE Gordon, A A Peden, M Lichtenberg, FM Menzies, B Ravikumar, S Imarisio, S Brown, CJ O’Kane, and DC Rubinsztein Alpha-synuclein impairs macroautophagy: implications for Parkinson’s disease. J. Cell Biol. 190, 1023-1037 (2010).
TJ van Ham, M Holmberg, A van der Goot, E Teuling, M Garcia-Arencibia, H Kim, D Du, KL Thijssen, M Wiersma, R Burggraaff, P van Bergeijk, J van Rheenen, G Jerre van Veluw, RMW Hofstra, DC Rubinsztein and EAA Nollen. Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity. Cell 142, 601-612 (2010).
VI Korolchuk, A Mansilla, FM Menzies and DC Rubinsztein Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol. Cell 33, 517-527 (2009).
A Williams, S Sarkar, P Cuddon, EK Ttofi, S Saiki, FH. Siddiqi, L Jahreiss, A Fleming, D Pask, P Goldsmith, CJ O’Kane, RA Floto and DC Rubinsztein Novel targets for Huntington’s disease in an mTOR-independent autophagy pathway. Nature Chem. Biol. 4, 295-305 (2008).
S Sarkar, EO Perlstein, S Imarisio, S Pineau, A Cordenier, RL Maglathlin, JA Webster, TA Lewis, CJ O’Kane, SL Schreiber, and DC Rubinsztein Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nature Chem. Biol. 3, 331-338 (2007).
S Sarkar, RA Floto, Z Berger, S Imarisio, A Cordenier, M Pasco, LJ Cook and DC Rubinsztein. Lithium induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 170, 1101-1111 (2005).
B Ravikumar, A Acevedo-Arozena, S Imarisio, Z Berger, C Vacher, CJ O’Kane, SDM Brown and DC Rubinsztein Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature Genetics 37, 771-776 (2005).
S Luo, C Vacher, JE Davies and DC Rubinsztein Cdk5 phosphorylation of huntingtin reduces its cleavage by caspases: implications for mutant huntingtin toxicity. J Cell Biol. 169, 647-656 (2005).
JE Davies, L Wang, L Garcia-Oroz, LJ Cook, C Vacher, DG O’Donovan and DC Rubinsztein. Doxycycline attenuates and delays toxicity of the oculopharyngeal muscular dystrophy mutation in transgenic mice. Nature Med. 6, 672-677 (2005).
B Ravikumar, C Vacher, Z Berger, JE Davies, S Luo, LG Oroz, F Scaravilli, DF Easton, R Duden, CJ O’Kane, and DC Rubinsztein. mTOR inhibition induces autophagy and reduces toxicity of the Huntington’s disease mutation in Drosophila and mouse models. Nature Genetics 36, 585-595 (2004).