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Mutations in the genes encoding LRRK2 and α-synuclein cause autosomal dominant forms of familial Parkinson's disease (PD). Fibrillar forms of α-synuclein are a major component of Lewy bodies, the intracytoplasmic proteinaceous inclusions that are a pathological hallmark of idiopathic and certain familial forms of PD. LRRK2 mutations cause late-onset familial PD with a clinical, neurochemical and, for the most part, neuropathological phenotype that is indistinguishable from idiopathic PD. Importantly, α-synuclein-positive Lewy bodies are the most common pathology identified in the brains of PD subjects harboring LRRK2 mutations. These observations may suggest that LRRK2 functions in a common pathway with α-synuclein to regulate its aggregation. To explore the potential pathophysiological interaction between LRRK2 and α-synuclein in vivo, we modulated LRRK2 expression in a well-established human A53T α-synuclein transgenic mouse model with transgene expression driven by the hindbrain-selective prion protein promoter. Deletion of LRRK2 or overexpression of human G2019S-LRRK2 has minimal impact on the lethal neurodegenerative phenotype that develops in A53T α-synuclein transgenic mice, including premature lethality, pre-symptomatic behavioral deficits and human α-synuclein or glial neuropathology. We also find that endogenous or human LRRK2 and A53T α-synuclein do not interact together to influence the number of nigrostriatal dopaminergic neurons. Taken together, our data suggest that α-synuclein-related pathology, which occurs predominantly in the hindbrain of this A53T α-synuclein mouse model, occurs largely independently from LRRK2 expression. These observations fail to provide support for a pathophysiological interaction of LRRK2 and α-synuclein in vivo, at least within neurons of the mouse hindbrain

Parkinson’s disease (PD) is the most common age-related neurodegenerative movement disorder that affects 1-2% of the general population over the age of 65 and rising to 4-5% over 80 years of age. It is estimated that 6.3 million people worldwide have Parkinson’s disease and 1.2 million in the European Union (EU) alone. As the disease progresses, patients frequently develop a mask-like facial expression, festinating gait and cognitive impairment and the final clinical symptoms are muscle rigidity, bradykinesia, resting tremor and postural instability in addition to non-motor problems that result in a marked reduction in quality of life. The motor symptoms of PD arise from the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) leading to a deficiency of the neurotransmitter dopamine (DA) in the striatum. While dopamine replacement therapy is initially effective in treating the motor symptoms of PD, there is no known cure or neuroprotective therapy for this debilitating disease. Although the pathology underlying the disease is well defined, it is still unclear why DAergic neurons degenerate and die. PD is generally considered as a sporadic disease of unknown etiology, however in the last two decades it has become clear that heritability plays an important role in the pathogenesis of PD. Of the different genes associated with familial disease, mutations in two genes encoding for α-synuclein and leucine-rich repeat kinase 2 (LRRK2) proteins cause autosomal dominant PD. One of the neuropathological hallmarks of idiopathic and some familial forms of PD are Lewy bodies, which are intracytoplasmic inclusions that are enriched with fibrillar α- synuclein protein. Notably, LRRK2 mutation carriers with PD predominantly develop Lewy body pathology suggesting that LRRK2 may lie upstream of α-synuclein aggregation. These observations and other in vivo studies have suggested a common pathogenic pathway with LRRK2 potentially regulating the aggregation and neuronal toxicity of α-synuclein. However, the relationship between LRRK2 and α-synuclein in the mammalian brain is presently unclear and requires further evaluation, especially within midbrain dopaminergic neurons that degenerate in PD. The aim of this thesis work was to delineate a potential pathogenic interplay between these two PD-related gene products in mediating neurodegeneration in vivo. Understanding how and where the functional pathways of LRRK2 and α-synuclein converge will provide important insight into the common mechanisms underlying neurodegeneration in PD.[...]

Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against a-synuclein-induced toxicity in cellular and invertebrate models of PD. Using a primary cortical neuronal model combined with lentiviral-mediated gene transfer, we demonstrate that human ATP13A2 isoforrns 1 and 2 display selective neuroprotective effects toward toxicity induced by manganese and hydrogen peroxide exposure through an ATPase-independent mechanism. The familial PD mutations, F182L and G504R, abolish the neuroprotective effects of ATP13A2 consistent with a loss-of-function mechanism. We further demonstrate that the MV-mediated overexpression of human ATP13A2 is not sufficient to attenuate dopaminergic neurodegeneration, neuropathology, and striatal dopamine and motoric deficits induced by human a-synuclein expression in a rat model of PD. Intriguingly, the delivery of an ATPase-deficient form of ATP13A2 (D513N) to the substantia nigra is sufficient to induce dopaminergic neuronal degeneration and motor deficits in rats, potentially suggesting a dominant-negative mechanism of action. Collectively, our data demonstrate a distinct lack of ATP13A2-mediated protection against alpha-synuclein-induced neurotoxicity in the rat nigrostriatal dopaminergic pathway, and limited neuroprotective capacity overall, and raise doubts about the potential of ATP13A2 as a therapeutic target for PD. (C) 2015 Elsevier Inc. All rights reserved.

Mutations in LRRK2 cause autosomal dominant Parkinson's disease (PD). LRRK2 encodes a multi-domain protein containing GTPase and kinase domains, and putative protein–protein interaction domains. Familial PD mutations alter the GTPase and kinase activity of LRRK2 in vitro. LRRK2 is suggested to regulate a number of cellular pathways although the underlying mechanisms are poorly understood. To explore such mechanisms, it has proved informative to identify LRRK2-interacting proteins, some of which serve as LRRK2 kinase substrates. Here, we identify common interactions of LRRK2 with members of the dynamin GTPase superfamily. LRRK2 interacts with dynamin 1–3 that mediate membrane scission in clathrin-mediated endocytosis and with dynamin-related proteins that mediate mitochondrial fission (Drp1) and fusion (mitofusins and OPA1). LRRK2 partially co-localizes with endosomal dynamin-1 or with mitofusins and OPA1 at mitochondrial membranes. The subcellular distribution and oligomeric complexes of dynamin GTPases are not altered by modulating LRRK2 in mouse brain, whereas mature OPA1 levels are reduced in G2019S PD brains. LRRK2 enhances mitofusin-1 GTP binding, whereas dynamin-1 and OPA1 serve as modest substrates of LRRK2-mediated phosphorylation in vitro. While dynamin GTPase orthologs are not required for LRRK2-induced toxicity in yeast, LRRK2 functionally interacts with dynamin-1 and mitofusin-1 in cultured neurons. LRRK2 attenuates neurite shortening induced by dynamin-1 by reducing its levels, whereas LRRK2 rescues impaired neurite outgrowth induced by mitofusin-1 potentially by reversing excessive mitochondrial fusion. Our study elucidates novel functional interactions of LRRK2 with dynamin-superfamily GTPases that implicate LRRK2 in the regulation of membrane dynamics important for endocytosis and mitochondrial morphology.

Soil development and erosion are important and opposing processes in the evolution of high-mountainous landscapes, though their dynamics are not fully understood. We compared soil development between a calcareous and a siliceous chronosequence in the central Swiss Alps at high altitudes, which both cover soil formation over the Holocene. We calculated element mass balances, long-term erosion rates based on meteoric 10Be and we determined the rates of soil formation. We also analyzed the shifts in the mineralogical composition, weathering indices, the particle size distribution, carbon stocks and oxalate extractable Fe, Al, and Mn. The siliceous soils had high chemical weathering rates at the early stage of soil formation that strongly decreased after a few millennia. The development of calcareous soil was characterized by high carbonate losses and a shift to finer soil texture. Soil erosion hampered the upbuilding of soil horizons in the early stages of soil development, which led to a delay in soil and vegetation development. This study shows how soil formation drivers change over time. In the early stages of soil development, the parent material predominantly drives soil formation while at later stages the vegetation becomes more dominant as it influences surface stability, hydrological pathways, and chemical weathering that determine water drainage and retention., Geosciences, 12 (2), ISSN:2076-3263

High mountainous areas are geomorphologically active environments which are strongly shaped by redistribution of sediments and soils. With the projected climate warming in the twenty‐first century and the continued retreat of glaciers, the area of newly exposed, highly erodible sediments and soils will increase. This presents a need to better understand and quantify erosion processes in young mountainous soils, as an increase in erodibility could threaten human infrastructure (i.e. hydroelectric power, tourist installations and settlements). While soil development is increasingly well understood and quantified, a coupling to soil erosion rates is still missing. The aim of this study was, therefore, to assess how soil erosion rates change with surface age. We investigated two moraine chronosequences in the Swiss Alps: one in the siliceous periglacial area of Steingletscher (Sustenpass), with soils ranging from 30 a to 10 ka, and the other in the calcareous periglacial area of Griessgletscher (Klausenpass) with surfaces ranging from age of 110 a to 13.5 ka. We quantified the erosion rates using the 239+240Pu fallout radionuclides and compared them to physical and chemical soil properties and the vegetation coverage. We found no significant differences between the two parent materials. At both chronosequences, the erosion rates were highest in the young soils (on average 5−10 t ha‐1 a‐1 soil loss). Erosion rates decreased markedly after 3−5 ka of soil development (on average 1−2.5 t ha‐1 a‐1 soil loss) to reach a more or less stable situation after 10−14 ka (on average 0.3–2 t ha‐1 a‐1). Climate change not only causes glacier retreat, but also increased sediment dynamics. Depending on the relief and vegetational development, it takes up to at least 10 ka to reach soil stability. The establishment of a closed vegetation cover with dense root networks seems to be the controlling factor in the reduction of soil erodibility.