DRPLA Pathway
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DRPLA Pathway

DRPLA (Dentatorubropallidoluysian Atrophy) is a Rare Neurodegenerative disorder that usually is inherited in an Autosomal Dominant pattern. The Clinical symptoms are variable depending on the age of onset of the disease Myoclonus, Epilepsy, and Mental Retardation are the main symptoms in Juvenile Onset, whereas Cerebellar Ataxia, Choreoathetosis, and Dementia are seen in Adult Onset. Neuropathologically, a combined degeneration of the Dentatorubral and Pallidoluysian systems is a characteristic feature of DRPLA. The disease is caused by an expansion of a CAG trinucleotide repeat encoding PolyQ (Polyglutamine) in the Atrophin-1 gene, on Chromosome 12 (Ref.1).

Atrophin-1, the DRPLA gene product, encodes a Hydrophilic 1184-amino acid protein with several simple repetitive motifs, including a Serine-rich region, a variable length PolyQ tract, a Polyproline tract, and a region of Alternating Acidic and Basic residues. The sequence of Atrophin-1 contains a putative NLS (Nuclear Localization Sequence) in its N-terminus and a putative NES (Nuclear Export Sequence) in its C-terminus. Atrophin-1 is expressed widely in brains of normal and affected individuals. Degeneration and cell death in DRPLA occurs mainly in the dentate nucleus of the Cerebellum, Red Nucleus, Globus Pallidus, and Subthalamic Nucleus. The Atrophin-1 protein normally localizes to both the nucleus and cytoplasm of cells. Truncation disrupts the normal regulated pattern of shuttling of Atrophin-1 between the nucleus and cytoplasm. The truncation product may accumulate to a higher concentration in the nucleus, or may localize to a different nuclear compartment and interact with different proteins within the nucleus compared with the full-length mutant protein. Truncation can be Caspase dependent or Caspase independent. Atrophin-1contains a consensus Caspase3 cleavage site near the NH2 terminus of the protein, and the PolyQ tract is located in the middle of the protein. Caspase cleavage of Atrophin-1 modulates cytotoxicity and aggregate formation. Cleavage of Atrophin-1 at Asp109 by Caspases is critical for cytotoxicity because a mutant Atrophin-1 that is resistant to Caspase cleavage is associated with significantly decreased toxicity. Further, the altered cellular localization within the nucleus and aggregate formation associated with the expanded form of Atrophin-1 are completely suppressed by mutation of the Caspase cleavage site at Asp109. Generation of a short truncation fragment in a Caspase independent manner (which could diffuse into the nucleus) can also lead to the formation of nuclear inclusions and cellular toxicity. In the nucleus DRPLA protein interacts with several proteins and that these interactions play an important role in pathogenesis (Ref.2).

The RERE (Arginine-Glutamic Acid Dipeptide (RE) Repeats) and DRPLA proteins interact with each other. Arginine-Glutamic Acid dipeptide repeats (RE repeats) occur twice in the C-terminal portion of the DRPLA sequence. RERE also contains Arginine-Aspartic Acid (RD) dipeptide repeats and putative nuclear localization signal sequences, but no PolyQ tracts. The proximal RE repeat of the RERE and DRPLA proteins serves as the site of interaction in protein-protein binding. As this repeat consists of alternate acidic-basic amino acid residues, the side of Alpha-helix also displays an alternate acidic-basic nature in every seventh residue. RERE protein is localized predominantly in the nucleus. Moreover, when RERE is overexpressed, the distribution of endogenous DRPLA protein alters from the diffused to the speckled pattern in the nucleus so as to co-localize with RERE. More RERE protein is recruited into nuclear aggregates of the DRPLA protein with extended Polyglutamine than into those of pure Polyglutamine. These results reveal a function for the DRPLA protein in the nucleus and the RE repeat in the protein-protein interaction (Ref.3). Recently it was shown that Atrophin-1 interacts with the human IRSp53 (Insulin Receptor Substrate-p53). Insulin and IGF1 (Insulin-Like Growth Factor-1) have a role in Neurotransmission, one that is regionally specific. The strength of the interaction is reduced when Atrophin-1 contains the expanded PolyQ stretch. Normal function of the neurons that undergo neuropathologic changes in DRPLA requires the interaction of IRSp53 and Atrophin-1 in an Insulin Receptor-signaling cascade. An expanded PolyQ stretch in Atrophin-1, which reduces binding to IRSp53, would therefore result in an impairment of protective Insulin signaling, leading to activation of neurotoxic pathways only in the particular cells that express IRSp53 (Ref.4).

Atrophin-1 with expanded repeats, but not with normal repeats, can interact with CBP (CREB-Binding Protein) and interfere with CBP-mediated transcription, yielding toxicity. Full-length Atrophin-1 with a normal or expanded repeat did not alter CBP-mediated transcription or cause cellular toxicity. There was no effect on CBP transcription and no toxicity when this Atrophin-1 truncation construct had a normal repeat.  Mutant Atrophin-1 also targets TAFII130 (TBP-Associated Factor, RNA Polymerase II, 130-KD) and disrupts transcription by CREB (cAMP-Response Element-Binding Protein). CREB, like SP1, is a transcriptional activator protein known to engage TAFII130 as a coactivator partner (Ref.5 and 6). SUMO1 (Small Ubiquitin Related Modifier-1) is also implicated in the pathogenesis of DRPLA and accelerates aggregate formation and cell death. DRPLA protein with normal sized PolyQ tracts also binds to GAPD (Glyceraldehyde-3-Phosphate Dehydrogenase). Atrophin-1 may also bind to few AIPs (Atrophin-1 Interacting Proteins). (Ref.7). DRPLA protein can be phosphorylated by JNK (c-Jun NH2-terminal Kinase). Expanded PolyQ slightly reduced the affinity of JNK to the protein. Thus, the abnormal DRPLA protein seems to be slowly phosphorylated in a certain condition of JNK activation and may delay the process that is essential in keeping neurons alive (Ref.8). There is a discrepancy between clinical features and lesion distribution evaluated by neuronal loss in the Polyglutamine diseases including DRPLA. Neuronal Intranuclear Inclusion is a characteristic feature of the Polyglutamine diseases; however, its significance in the pathogenesis is still a matter of controversy (Ref.9).