Dario R. Alessi

Leucine-rich repeat kinase 2 impairs the release sites of Parkinson's disease vulnerable dopamine axons

This study identifies LRRK2's role in impairing dopamine axon release sites in Parkinson's disease, leading to reduced dopamine release and synaptic dysfunction.

Rare bi-allelic loss-of-function variants in the LRRK2 kinase cause interstitial lung disease

This study identifies biallelic LRRK2 loss-of-function variants as a cause of interstitial lung disease, showing reduced LRRK2 protein and impaired lung function in affected individuals.

Elucidating the molecular interplay between LRRK2 and Rab GTPases

This study identifies six distinct Rab-binding sites on LRRK2 and a GABARAP-binding site, revealing molecular mechanisms of Rab recognition and potential therapeutic targets for Parkinson's disease.

A Functional Genetic Atlas of Parkin Resolves Variants of Uncertain Significance and Predicts Parkinson's Disease Age at Onset

The paper functionally characterizes PRKN variants using a pooled assay, reclassifies variants of uncertain significance, and predicts Parkinson's disease age at onset.

Structural basis for binding of RILPL1 to TMEM55B reveals a lysosomal platform for adaptor assembly through a conserved TBM motif

This paper reports the crystal structures of TMEM55B and its complex with a RILPL1 peptide, revealing a conserved TBM motif that mediates adaptor recruitment to lysosomes.

Alternative Splicing Directs PMCA2 to Lysosomes and is Linked to Neurodegeneration

The paper identifies a splice variant-dependent localization of PMCA2 to lysosomes and links it to neurodegenerative diseases.

TDP-43 loss of function drives aberrant splicing in Parkinson's disease

The paper identifies splicing dysregulation in Parkinson's disease linked to TDP-43 loss of function and shows its association with genetic mutations and cellular models.

PPM1M, a LRRK2-counteracting, phosphoRab12-preferring phosphatase with potential link to Parkinsons disease

The paper identifies PPM1M as a phosphatase that reverses LRRK2-mediated Rab phosphorylation and links a rare mutation to Parkinson's disease.

NRBP1 and TSC22D proteins impact distal convoluted tubule physiology through modulation of the WNK pathway

This study shows NRBP1 and TSC22D proteins modulate WNK signaling in the kidney's distal convoluted tubule, affecting Na+ reabsorption through NCC phosphorylation.

NRBP1 pseudokinase binds to and activates the WNK pathway in response to osmotic stress

This study identifies NRBP1 as an upstream activator of the WNK pathway by forming a multi-subunit complex with WNK1, SPAK, and TSC22D4 in response to osmotic stress.

Restoration of striatal neuroprotective pathways by kinase inhibitor treatment of Parkinsons linked-LRRK2 mutant mice

The paper shows that LRRK2 kinase inhibitor treatment restores cilia, Hedgehog signaling, neuroprotective factors, and dopamine processes in Parkinson's linked-LRRK2 mutant mice striatum.

C9orf72 polyGA knock-in mice exhibit mild motor and proteomic changes consistent with ALS/FTD

This study creates (GA)400 knock-in mice to model C9orf72 polyGA expression, finding mild motor dysfunction and proteomic changes in the spinal cord.

Regulation of Leucine-Rich Repeat Kinase 2 by inflammation and IL-4

This study investigates how inflammation and IL-4 regulate LRRK2 expression and activity in immune cells, revealing cell-specific effects and the role of the LRRK2-R1441C mutation.

Lysosome damage triggers acute formation of ER to lysosomes membrane tethers mediated by the bridge-like lipid transport protein VPS13C

The paper shows that VPS13C senses lysosome damage, relocates to lysosomes, and tethers them to the ER, suggesting a protective lipid transport response.

Endogenous LRRK2 and PINK1 function in a convergent neuroprotective ciliogenesis pathway in the brain

This study shows LRRK2 and PINK1 function in parallel neuroprotective pathways affecting ciliogenesis in Parkinson's disease, suggesting shared therapeutic targets.

Tagless LysoIP method for molecular profiling of lysosomal content in clinical samples

The paper develops a tagless LysoIP method to isolate lysosomes from clinical samples and human cell lines, revealing glycerophosphodiesters as potential biomarkers for lysosomal storage disorders.

Loss of primary cilia and dopaminergic neuroprotection in pathogenic LRRK2-driven and idiopathic Parkinsons disease

The paper shows that loss of primary cilia in specific striatal cell types reduces dopaminergic neuroprotection in Parkinson's disease, linked to impaired Hedgehog signaling.

CURTAIN - A Unique Web-based tool for exploration and sharing of MS-based proteomics data

CURTAIN and CURTAIN-PTM are web-based tools for exploring and sharing MS-based proteomics data, enabling non-experts to analyze and visualize results through interactive features and shareable links.

Parkinsons VPS35 mutation induces LRRK2 mediated lysosomal association of RILPL1 and TMEM55B

This study shows that the VPS35[D620N] mutation causes lysosomal dysfunction, activates LRRK2, and promotes the lysosomal association of RILPL1 and TMEM55B through phosphorylation of Rab proteins.

PolyGR and polyPR knock-in mice reveal a conserved neuroprotective extracellular matrix signature in C9orf72 ALS/FTD neurons

The paper generates C9orf72 DPR knock-in mice and identifies an extracellular matrix signature in C9ALS/FTD that is conserved across species and protected by TGF-β1 and COL6A1.

Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration

This study shows that C9orf72 mutations disrupt autophagy in microglia, leading to immune dysfunction and increased motor neuron death in ALS/FTD.

Protein aggregation and calcium dysregulation are the earliest hallmarks of synucleinopathy in human midbrain dopaminergic neurons

This study uses hiPSCs with SNCA mutations to identify early molecular events in synucleinopathy, showing protein aggregation precedes functional impairments in midbrain dopaminergic neurons.

Impact of 100 LRRK2 variants linked to Parkinsons Disease on kinase activity and microtubule binding

This study evaluates 100 LRRK2 variants linked to Parkinson's disease, identifying those that enhance kinase activity and microtubule binding, and highlights their implications for clinical trials.

Sequence and structural variations determining the recruitment of WNK kinases to the KLHL3 E3 ligase

This paper determines the crystal structure of KLHL3 in complex with a WNK3 peptide, revealing structural features and phosphorylation-dependent regulation of WNK3 binding.

A mitochondrial blood-based patient stratification candidate biomarker for Parkinson's disease

The paper identifies mtDNA damage as a blood-based biomarker for Parkinson's disease, showing increased levels in early-stage patients and mutation carriers, suggesting its potential for patient stratification in clinical trials.

Impact of Type II LRRK2 inhibitors on signalling and mitophagy

This study compares Type I and Type II LRRK2 inhibitors, showing Type II compounds are more potent against wild-type LRRK2 and fail to dephosphorylate specific biomarker sites, suggesting conformational selectivity.

Development of a multiplexed targeted mass spectrometry assay for LRRK2 phosphorylated Rabs and Ser910/Ser935 biomarker sites

The paper develops and validates a multiplexed mass spectrometry assay to quantify LRRK2-phosphorylated Rab proteins and biomarker sites, showing VPS35[D620N] enhances Rab1 phosphorylation in Parkinson's disease.

Endogenous Rab29 does not impact basal or nigericin and monensin stimulated LRRK2 pathway activity

This study shows that Rab29 does not regulate basal or nigericin/monensin-induced LRRK2 pathway activity in mice.