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Parkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73. Here, we evaluated the contribution of c-Abl and p73 in the degeneration of dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine as a model for Parkinson's disease. First, we found that in SH-SY5Y cells treated with 6-hydroxydopamine, c-Abl and p73 phosphorylation levels were up-regulated. Also, we found that the pro-apoptotic p73 isoform TAp73 was up-regulated. Then, to evaluate whether c-Abl tyrosine kinase activity is necessary for 6-hydroxydopamine-induced apoptosis, we co-treated SH-SY5Y cells with 6-hydroxydopamine and Imatinib, a c-Abl specific inhibitor, observing that Imatinib prevented p73 phosphorylation, TAp73 up-regulation, and protected SH-SY5Y cells treated with 6-hydroxydopamine from apoptosis. Interestingly, this observation was confirmed in the c-Abl conditional null mice, where 6-hydroxydopamine stereotaxic injections induced a lesser reduction of dopaminergic neurons than in the wild-type mice significantly. Finally, we found that the intraperitoneal administration of Imatinib prevented the death of dopaminergic neurons induced by injecting 6-hydroxydopamine stereotaxically in the mice striatum. Thus, our findings support the idea that the c-Abl/p73 pathway is involved in 6-hydroxydopamine degeneration and suggest that inhibition of its kinase activity might be used as a therapeutical drug in Parkinson's disease.

Abstract Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.

Background: Mycosis fungoides (MF) is a cutaneous T-cell lymphoma that disproportionately affects people with skin of color and is difficult to diagnose. Objective: This study characterized the dermoscopic features of MF and its subtypes in patients with skin of color. Methods: Dermoscopic images of patients with skin of color seen at the cutaneous T-cell lymphoma clinic at Michigan Medicine Dermatology between 2018 and 2019 were reviewed. Specific dermoscopic features were identified and summarized for each subtype of MF. Results: A total of 33 dermoscopic images from 11 patients with skin of color were reviewed. Four patients had classic MF (18 dermoscopic images), 4 had hypopigmented MF (9 dermoscopic images), 1 had folliculotropic MF (4 dermoscopic images), and 2 had verrucous MF (2 dermoscopic images). Classic MF was characterized by striking pigmentary change, thick black lines, white rosettes, and geometric white lines. Hypopigmented MF was characterized by the loss of the patient’s natural pigment network. In folliculotropic MF, follicular plugging and hyperpigmented to violaceous perifollicular halos were observed. In verrucous MF, large, yellow-gray amorphous structures with yellow-gray ridges and comedo-like openings were observed within hyperkeratotic areas. Overall, vessel morphology was difficult to discern on dermoscopy. Conclusions: Dermoscopic features of MF in patients with skin of color are predominantly characterized by striking pigmentary alteration. Vessel morphology is not a reliable diagnostic feature. As patients with MF and skin of color have a worse prognosis than light-skinned individuals, a better understanding of dermoscopic features may aid in early diagnosis and improve outcomes in this group.