Hereditary parkinsonism with dementia, known as Kufor-Rakeb syndrome (KRS), is caused by mutations in the *ATP13A2* gene, encoding a lysosomal type 5 P-type ATPase. This gene is predominantly expressed in neurons, particularly in the brain. The study identified two different mutations in a Chilean family with early-onset Parkinson disease, which were also found in a Jordanian family with KRS. These mutations result in the retention of unstable, truncated proteins in the endoplasmic reticulum and their enhanced proteasomal degradation, leading to neurodegeneration. The findings link *ATP13A2* to the molecular pathophysiology of parkinsonism and dementia, highlighting the importance of this previously uncharacterized gene in neurodegenerative disorders.Hereditary parkinsonism with dementia, known as Kufor-Rakeb syndrome (KRS), is caused by mutations in the *ATP13A2* gene, encoding a lysosomal type 5 P-type ATPase. This gene is predominantly expressed in neurons, particularly in the brain. The study identified two different mutations in a Chilean family with early-onset Parkinson disease, which were also found in a Jordanian family with KRS. These mutations result in the retention of unstable, truncated proteins in the endoplasmic reticulum and their enhanced proteasomal degradation, leading to neurodegeneration. The findings link *ATP13A2* to the molecular pathophysiology of parkinsonism and dementia, highlighting the importance of this previously uncharacterized gene in neurodegenerative disorders.