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, 18 (9), 1705-11

Impaired Autophagy: A Link Between Neurodegenerative and Neuropsychiatric Diseases


Impaired Autophagy: A Link Between Neurodegenerative and Neuropsychiatric Diseases

Mira Polajnar et al. J Cell Mol Med.


Protein misfolding, and subsequent aggregation have been proven as the leading cause of most known dementias. Many of these, in addition to neurodegeneration, show profound changes in behaviour and thinking, thus, psychiatric symptoms. On the basis of the observation that progressive myoclonic epilepsies and neurodegenerative diseases share some common features of neurodegeneration, we proposed autophagy as a possible common impairment in these diseases. Here, we argue along similar lines for some neuropsychiatric conditions, among them depression and schizophrenia. We propose that existing and new therapies for these seemingly different diseases could be augmented with drugs used for neurodegenerative or neuropsychiatric diseases, respectively, among them some which modulate or augment autophagy.

Keywords: autophagy; neurodegenerative diseases; progressive myoclonus epilepsies; protein aggregation; psychiatric diseases.


Fig. 1
Fig. 1
The signalling pathways connected to autophagy. Phosphatidylinositol signalling pathway is regulated by Class I phosphoinositide 3-kinases (PI3Ks), which are activated by kinase receptors like insulin receptors (IR) and responsible for the production of phosphatidylinositol (3,4,5)-triphosphate (PIP3) from phosphatidylinositol 4,5-bisphosphate (PIP2). Phospholipase C (PLC) cleaves the PIP2 into diacyl glycerol and inositol 1,4,5-trisphosphate (IP3). Inositol polyphosphate 1-phosphatase (IPPase) catalyses inositol bisphosphate (IP2) to inositol monophosphate (IP), which is further dephosphorylated by inositol monophosphatase (IMPase) to inositol. High-affinity inositol transport is additionally catalysed by the active myo-inositol/H+ transporter (MIT). MIT, IPPase and IMPase are all inhibited by carbamazepine (CBZ), valproic acid (VPA) and lithium (Li+). PI3Ks have been linked to an extraordinarily diverse group of cellular functions through regulation of the Akt/TSC1-TSC2/mTOR pathway. Disrupted in Schizophrenia 1 (DISC1) in its wild-type form also negatively regulates both GSK3β and Akt (also known as Protein Kinase B, PKB). Tuberous sclerosis protein 1 and 2 (TSC1/2) form a complex that like rapamycin (Rap) inhibits mammalian target of rapamycin kinase (mTOR). Wnt signalling activation is mediated through binding of a Wnt-protein ligand to a Frizzled family receptor, which passes the biological signal to the protein Dishevelled (Dsh). Dsh negatively regulates glycogen synthase kinase-3 beta (GSK3β), which alternatively inhibits β-catenin, one of the central proteins of the Wnt signalling pathway. β-catenin, however, negatively regulates LKB1/AMPK pathway (liver kinase B1/5' adenosine monophosphate-activated protein kinase) that indirectly regulates autophagy.

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