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The 2016 Nobel Prize winning cellular mechanism, autophagy, and neurodegeneration

Annalise Barnette
Nov 11, 2016

More than 27 years ago, Professor Yoshinori Ohsumi’s penchant for observing yeast vacuoles under the microscope led to breakthroughs in our understanding of the cellular destruction process known as autophagy (Greek: auto = self and phagy = eating) (Takeshige et al. 1992, Deter and de Duve 1967, Glick et al. 2010). It was for his discoveries of the mechanisms underlying autophagy that he won the 2016 Nobel Prize in Medicine on October 3, 2016.

Autophagy is a highly conserved process in which cellular components or intracellular pathogens are encapsulated in structures called autophagosomes and then degraded and recycled in lysosomes or vacuoles (Deter and de Duve 1967, Glick et al. 2010). It was first considered to exclusively occur in response to starvation. However our understanding of the process has rapidly increased and misregulation has been associated with a variety of diseases including cancer and neurodegeneration.

In recent years, the role of autophagy in neurodegeneration, particularly in the context of developing therapies for neurodegenerative diseases, has received special attention (Komatsu et al. 2006, Hara et al. 2006). This is largely due to studies showing that disruption of neuronal cell health through the accumulation of aggregated proteins is associated with neurodegeneration (Ross and Poirier 2004). Intracellular aggregates of misfolded proteins are common characteristics of many neurodegenerative diseases such as Parkinson’s disease and Huntington’s disease (Frake et al. 2015). Furthermore, accumulation of ubiquitinated proteins have been linked to late-onset neurodegenerative diseases such as Alzheimer’s disease (Vernace et al. 2007).

The ubiquitin-proteasome system is primarily responsible for the degradation of misfolded proteins. However, the proteasome cannot degrade the stable protein aggregates common in neurodegenerative diseases (Venkatraman et al. 2004). The macroautophagy process has been implicated as a powerful compensatory mechanism for clearing these aggregated proteins (learn more about macroautophagy here). This finding has led to increased interest in understanding the mechanisms by which autophagy removes aggregates and whether induction of autophagy could reverse neurodegeneration.

One proposed mechanism of autophagy mediated clearance of protein aggregates involves the sequestosome protein p62/SQSTM1, encoded by the SQSTM1 gene. p62 is a polyubiquitin binding protein that sequesters ubiquitinated proteins and targets them for destruction by the autophagy system (Matsumoto et al. 2011). It has been detected in neuronal protein aggregates that induce neurodegenerative diseases in mouse and human models (Zatloukal et al. 2002). It functions as an autophagy modifier of the MAP1 LC3 family, and has been identified as a key mediator of autophagy induced clearance of aggregate protein complexes.

Under non-disease conditions, p62 is maintained in equilibrium between phosphorylated and dephosphorylated states. As polyubiquitinated proteins accumulate in neuronal cells due to 26S proteasome inhibition or overload, p62 (phosphorylated at serine 403 by casein kinase 2 (CK2)) binds to the ubiquitinated protein aggregates thereby targeting them for autophagy. Once cargo-bound, p62 becomes resistant to dephosphorylation (Matsumoto et al. 2011).

Upregulation/induction of p62 mediated-autophagic clearance of polyubiquitinated protein aggregates is therefore considered as a potential therapy for treating neurodegenerative diseases. This is supported by several studies, which have provided proof-of-principle for the induction of autophagy as therapy for neurodegeneration (Frake 2015). In fact a number of US FDA-approved drugs that ameliorate neurodegenerative pathology through upregulation of autophagy have been identified (Frake et al. 2015).

One such drug is the antihypertensive medicine rilmenidine, which acts through Gi-coupled imidazoline receptors (Reid 2000). Rilmenidine was shown to promote clearance of aggregate-prone proteins and improve neurodegenerative pathology in primary human neurons and mouse models of Huntington’s disease (Rose et al. 2010). Based on this finding, a clinical trial to assess its safety is on-going in patients with Huntington’s disease (EudraCT number 2009-018119-14).

Upregulation of autophagy as a therapeutic strategy for neurodegenerative diseases is therefore very promising. However, as Professor Ohsumi stated in his interview after receiving notice of his Nobel Prize, in discussing autophagy, “still we have so many questions.” Further understanding of the mechanisms controlling autophagic clearance of protein aggregates in neurodegeneration is required to produce more selective and targeted therapies.

References

Deter RL and de Duve C (1967). Influence of glucagon, an inducer of cellular autophagy, on some physical properties of rat liver lysosomes. J Cell Biol 33, 437-449.

Frake RA et al. (2015). Autophagy and neurodegeneration J Clin Invest 125, 65-74.

Glick D et al. (2010). Autophagy: cellular and molecular mechanisms. J Pathol 221, 3-12.

Hara T et al. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885-889.

Komatsu M et al. (2006). Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441, 880-884.

Matsumoto G et al. (2011). Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins. Mol Cell 44, 279-289.

Reid JL (2000). Rilmenidine: a clinical overview. Am J Hypertens 13, 106S-111S.

Rose C et al. (2010). Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington’s disease. Hum Mol Genet 19, 2144-2153.

Ross CA and Poirier MA (2004). Protein aggregation and neurodegenerative disease. Nat Med 10 Suppl, S10- S7.

Takeshige K et al. (1992). Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119, 301-311.

Venkatraman P et al. (2004). Eukaryotic proteasomes cannot digest polyglutamine sequences and release them during degradation of polyglutamine-containing proteins. Mol Cell 14, 95-104.

Vernace VA et al. (2007). Aging and regulated protein degradation: who has the UPPer hand? Aging Cell 6, 599-606.

Zatloukal K et al. (2002). p62 is a common component of cytoplasmic inclusions in protein aggregation diseases. Am J Pathol 160, 255-263.

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