PKR or Protein Kinase R is an interferon-induced, double stranded RNA (dsRNA)-activated eIF2α kinase that is a key regulator of cellular stress response pathways. PACT (also known as PRKRA, and DYT16) activates PKR in response to oxidative stress, endoplasmic reticulum (ER) stress, and serum starvation. Prolonged PKR activation in response to cellular stress leads to cell death by apoptosis. An inherited form of early-onset dystonia has been identified to be associated with multiple mutations in the coding region of PACT. Dystonia is a neurological disorder defined by an occurrence of sustained involuntary muscle contractions, often leading to disabling and abnormal postures. Several recessive missense mutations and one dominant frame-shift mutation in PACT have been identified to result in dystonia. A German patient was recently identified as having a heterozygous mutation in exon 3 of PACT (AT deletion at c.266-267) creating a premature stop codon, resulting in a truncation at AA position 109. The main hypothesis of this research is that the frame-shift mutation in PACT leads to production of a truncated protein that is misfolded and forms aggregates resulting in cellular stress and the disease phenotype. We compared the ability of wild type PACT and frame-shift (FS) PACT proteins to interact with and activate PKR using in vitro biochemical assays. In addition, we have investigated changes in sub-cellular localization, protein aggregation, and cell death resulting from FS PACT mutant. Our results indicate that although FS PACT lacks the PKR activation domain, it activates PKR robustly in vitro because it forms aggregates. In addition, the truncated FS mutant protein also exhibits altered sub-cellular localization and forms aggregates in mammalian cells. These results raise a possibility that the PKR activation observed in several neurodegenerative diseases that are caused by protein aggregation may be an important contributing factor for the disease pathology.