Impaired autophagy: a link between neurodegenerative diseases and progressive myoclonus epilepsies Mira Polajnar and Eva Z ˇ erovnik Department of Biochemistry, Molecular and Structural Biology, Joz ˇef Stefan Institute, Jamova 39, 1000 Ljubljana, Slovenia In recent years, research into the molecular bases of neurodegenerative diseases has progressed, and thera- pies have been developed to combat the causative agents. Based on the observation that progressive my- oclonus epilepsies (PMEs) and neurodegenerative dis- eases share common features of neurodegeneration, we propose that the two pathologies share common under- lying molecular characteristics. It is well documented that autophagy is overloaded or impaired in neurode- generative conditions, and it is also impaired in some PMEs, the clearest example being EPM2 (Lafora disease). Although more research into this connection is war- ranted, we propose that existing therapies for PMEs could be augmented with similar drugs as those used for neurodegenerative diseases. Autophagy impairment is shared between neurodegenerative diseases (NDs) and progressive myoclonus epilepsies (PMEs) Undoubtedly, NDs, whose frequencies increase with aging, place a considerable burden on society. Whereas NDs such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are in most cases sporadic and associated with multiple genetic abnormalities, each presenting a risk factor, PMEs are monogenic, familial syndromes [1]. Although PMEs are rare diseases, they nevertheless place an immense burden on inflicted families. Like the more severe familial forms of NDs, PMEs are progressive and some lead to dementia and death early in life [1]. Links can be found between the pathologies of NDs and PMEs. On the one hand, features of neurodegeneration appear in PMEs, leading to oxidative stress and the apop- tosis of certain brain regions. On the other hand, NDs such as AD, Huntington’s disease (HD) and dementia with Lewy bodies are associated with increased incidences of epileptic seizures [2]. A comparison between PMEs and NDs reveals that common features, such as ataxia and myoclonus (i.e. involuntary twitching of muscles), appear at more severe stages of most such diseases, with different severities of certain symptoms seen in each individual disease. We suggest that the common symptoms of PMEs and NDs might reflect a common cellular and molecular pa- thology (Figure 1). Specifically, impaired autophagy could be common to most PMEs, a characteristic shared with NDs. Given the similarities between NDs and PMEs, probing and targeting autophagy could be helpful for PME patients, at least as an adjunct therapy. PMEs PMEs are a heterogeneous group of inherited monogenic disorders that share a combination of myoclonus, epilepsy and often progressive neurological and cognitive deterio- ration [1]. PMEs comprise five disorders: EPM1 (Unver- richt–Lundborg disease), EPM2 (Lafora body disease), ragged red fibers syndrome (MERRF), neuronal ceroid lipofuscinoses (NCLs) and type I sialidosis (Table 1). There are many differences in the age of onset of these diseases and in the severity of clinical manifestations. For instance, whereas EPM2 and NCLs lead to death in the mid-to-late 20 s (or even very early in life), EPM1 patients can live to a normal old age [1,3] (Table 1). PME pathophysiology is also variable. In EPM1, the apoptosis of the cerebellar neurons, in particular the Pur- kinje cells [4], dysfunctional lysosomes [5] and oxidative stress [6] are present. The main feature in EPM2 is Lafora bodies, cellular structures in which aberrantly processed glycogen polymers, termed polyglucosans, accumulate (reviewed in [7]). NCLs and type I sialidosis are lysosomal storage diseases, also characterized by the accumulation of inclusions in neuronal cells. In particular, the excessive accumulation of lipopigments (lipofuscin) occurs together with some proteinaceous components in NCLs [8], whereas in sialidosis the abnormal accumulation of mucopolysac- charides and mucolipids is observed. Finally, MERRF is a mitochondrial disease in which dysfunctional mitochon- dria accumulate in the muscle fibers – termed ‘ragged red fibers’. In this disease, a maternally inherited mitochon- drial DNA mutation (encoding tRNA Lys) causes abnor- malities in the synthesis of proteins essential for oxidative phosphorylation [1,3]. In the following sections, we concen- trate on EPM1 and EPM2 because recent molecular re- search on the proteins that cause these two PMEs sheds light on the possible role of autophagy. EPM1 EPM1 is an autosomal recessive inherited disorder in which patients suffer from diffuse myoclonic jerks, gener- alized tonic–clonic seizures (which diminish over time) and a progressive increase in myoclonus [9,10]. Cognitive Opinion Corresponding author: Z ˇ erovnik, E. (eva.zerovnik@ijs.si). 1471-4914/$ – see front matter ß 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2011.02.005 Trends in Molecular Medicine, June 2011, Vol. 17, No. 6 293