Parkinson's disease is a progressive and debilitating neurodegenerative disease. The disease is caused by degeneration of dopamine neurons in the substantia nigra projecting to the dorsal striatum. These neurons are a crucial part of the circuitry controlling movement and motor learning. The classical motor symptoms of the disease are rigidity, tremor, postural instability and bradykinesia. All current drug treatments are symptomatic and do not modulate the progression of the disease.
The "dying back" degeneration of nigrostriatal dopamine neurons starts from the dorsal striatum and progresses towards cell bodies in the substantia nigra (Airavaara et al., 2014, Parkinsonism Relat Disord; Domanskyi et al., 2015, Human Gene Therapy). While the neurons are dying they first lose their dopamine phenotype, and neurons become metabolically inactive while cellular architecture is retained. We have shown that the dopamine phenotype can be restored with neurotrophic factors. Our research is focused on novel neurotrophic factors such as Cerebral Dopamine Neurotrophic Factor (CDNF), Mesencephalic Astrocyte-derived Neurotrophic Factor (MANF) as well as Glial cell line-Derived Neurotrophic Factor (GDNF) and its family members. Specifically, we are studying them to stop the progression of the disease (Airavaara et al., 2012 Cell Transplantation, Runeberg-Roos et al., 2015, Neurobiology of Disease; Huotarinen et al., 2018, Neuroscience; Penttinen et al., 2018, Frontiers of Neurology). Direct targets of the research are characterization of the dopamine phenotype, endoplasmic reticulum stress, and protein aggregation.
As models we are using primary dopamine neuron cultures as well as several disease models. The models are based on 6-hydroxydopamine, MPTP, lactacystin, and preformed alpha-synuclein protein fibrils. We have also characterized gene targeting to the striatum or substantia nigra with adeno-associated viral (AAV) vectors.
Drugs of abuse induce neuroadaptive processes in the brain that involve regulation of neurotrophic factors. Our research interests is in neurotrophic factors mediating function of dopamine neurons and addiction-related behavior (Airavaara et al., 2004, 2006, Koskela et al., 2017). In particular, we are interested in studying neurobiology of drug craving after withdrawal from drug self-administration (Pickens et al., 2011, Airavaara et al., 2011). We have recently developed a new method where alcohol craving can be studied in a social context and enviromental enrichment (Koskela et al., 2018), which we think is an essential tool for future neurobiological studies.