![]() ![]() Both genetic and environmental factors contribute to the development of PD 3, presenting challenges for identifying disease mechanisms that can be targeted therapeutically 4. However, aberrant AGE accumulation has also been linked to multiple human pathologies, including aging-related neurodegenerative diseases such as PD. The accumulation of such advanced glycation end products (AGEs) on nucleotides, lipids, and proteins is known to damage cell function and is a feature of normal aging 2. Recently, glycation, a process in which aldehyde metabolites and nucleophiles become attached to biopolymers through non-enzymatic reactions, has come into focus as a disease-driving mechanism. ![]() Accordingly, investigating how biological mechanisms of aging are interconnected with the progression of neurodegenerative diseases is an active research area with significant therapeutic potential. Similar content being viewed by othersĪging is the strongest risk factor for developing neurodegenerative diseases such as Alzheimer’s Disease (AD) and Parkinson’s Disease (PD) 1. In conclusion, astrocytes’ capacity to clear toxic damaged proteins is critical to preserve neuronal function and their dysfunction contributes to the neurodegeneration observed in a DJ1 loss-of-function PD model. Consistently, in co-cultures, we find that DJ1-expressing astrocytes are able to reverse the proteolysis deficits of DJ1 knockout midbrain neurons. We demonstrated these processes are at least partly driven by astrocytes, as DJ1 loss reduces their capacity to provide metabolic support and triggers acquisition of a pro-inflammatory phenotype. In induced pluripotent stem cell (iPSC)-derived midbrain organoid models deficient for DJ1 activity, we find that lysosomal proteolysis is impaired, causing AGEs to accumulate, α-synuclein (α-syn) phosphorylation to increase, and proteins to aggregate. Here, we studied how AGEs contribute to development of early onset Parkinson’s Disease (PD) caused by loss-of-function of DJ1, a protein deglycase. Accumulation of advanced glycation end products (AGEs) on biopolymers accompanies cellular aging and drives poorly understood disease processes. ![]()
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