A sporadic Parkinson's disease model via silencing of the ubiquitin-proteasome/E3 ligase component, SKP1A.

Our and other's laboratory microarray-derived transcriptomic studies in human PD substantia nigra pars compacta (SNpc) samples have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in sporadic PD (SPD). One emerging gene candidate identified was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc as confirmed later at the protein level. SKP1 is part of the Skp1, Cullin 1, F-box protein (SCF) complex, the largest known class of sophisticated ubiquitin-proteasome/E3-ligases and was found to directly interact with FBXO7, a gene defective in PARK15-linked PD.

Lewy bodies, iron, inflammation and neuromelanin: pathological aspects underlying Parkinson's disease.

Since the description of some peculiar symptoms by James Parkinson in 1817, attempts have been made to define its cause or at least to enlighten the pathology of "Parkinson's disease (PD)." The vast majority of PD subtypes and most cases of sporadic PD share Lewy bodies (LBs) as a characteristic pathological hallmark. However, the processes underlying LBs generation and its causal triggers are still unknown.

The role of tyrosine hydroxylase as a key player in neuromelanin synthesis and the association of neuromelanin with Parkinson's disease.

The dark pigment neuromelanin (NM) is abundant in cell bodies of dopamine (DA) neurons in the substantia nigra (SN) and norepinephrine (NE) neurons in the locus coeruleus (LC) in the human brain. During the progression of Parkinson's disease (PD), together with the degeneration of the respective catecholamine (CA) neurons, the NM levels in the SN and LC markedly decrease. However, questions remain among others on how NM is associated with PD and how it is synthesized.

The Neuroprotective Activities of the Novel Multi-Target Iron-Chelators in Models of Alzheimer's Disease, Amyotrophic Lateral Sclerosis and Aging.

The concept of chelation therapy as a valuable therapeutic approach in neurological disorders led us to develop multi-target, non-toxic, lipophilic, brain-permeable compounds with iron chelation and anti-apoptotic properties for neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), age-related dementia and amyotrophic lateral sclerosis (ALS). Herein, we reviewed our two most effective such compounds, M30 and HLA20, based on a multimodal drug design paradigm. The compounds have been tested for their mechanisms of action using animal and cellular models such as APP/PS1 AD transgenic (Tg) mice, G93A-SOD1 mutant ALS Tg mice, C57BL/6 mice, Neuroblastoma × Spinal Cord-34 (NSC-34) hybrid cells, a battery of behavior tests, and various immunohistochemical and biochemical techniques.